Claims:

1. A method of treating bronchial constriction in a patient comprising:
stimulating selected nerve fibers that control or mediate the dilation of
smooth muscle, wherein one or more pulses of energy are transmitted to
said nerve fibers to stimulate them non-invasively.

2. The method set forth in claim 1 wherein an electric current and/or an
electric field is induced by a time-varying magnetic field, wherein
energy derived from said electric current and/or said electric field
stimulates the selected nerve fibers, and wherein the energy of said
magnetic field is transmitted non-invasively.

4. The method set forth in claim 1 wherein energy derived from light or
heat stimulates the selected nerve fibers, wherein said light or said
heat is transmitted non-invasively.

5. The method set forth in claim 1 wherein energy derived from an electric
field and/or an electric current stimulates the selected nerve fibers,
and wherein the energy of said electric field and/or said electric
current is transmitted non-invasively through the lead of an electrode or
through an electrically-conducting garment.

6. The method of claim 1 wherein the selected nerve fibers are associated
with a vagus nerve of the patient.

7. The method of claim 1 wherein the selected nerve fibers are in a neck
of the patient.

8. The method of claim 1 wherein the selected nerve fibers are within a
carotid sheath of the patient.

9. The method of claim 1 wherein the selected nerve fibers are associated
with an auricular branch of a vagus nerve of the patient.

10. The method of claim 1 wherein the selected nerve fibers are in an
external auditory meatus of the patient.

11. The method of claim 1 wherein the selected nerve fibers control or
modulate the release of catecholamines.

12. The method of claim 11 wherein the selected nerve fibers control or
modulate the systemic release of catecholamines from an adrenal gland of
the patient.

17. The method of claim 1 wherein the bronchial constriction is associated
with an acute symptom of asthma.

18. The method of claim 1 wherein the bronchial constriction is associated
with an acute symptom of anaphylaxis.

19. The method of claim 1 wherein the bronchial constriction is associated
with an acute symptom of chronic obstructive pulmonary disease.

20. The method of claim 1 wherein the bronchial constriction is comorbid
with hypotension.

21. The method of claim 1 wherein the stimulating step is carried out
without substantially stimulating a second set of nerve fibers
responsible for increasing the magnitude of constriction of smooth
muscle.

22. The method of claim 1 further comprising blocking or inhibiting a
second set of nerve fibers responsible for increasing the magnitude of
constriction of smooth muscle.

23. The method of claims 21 wherein the second set of nerve fibers is
associated with a vagus nerve of the patient.

24. The method of claims 22 wherein the second set of nerve fibers
comprises parasympathetic cholinergic nerve fibers.

25. The method of claim 1 wherein the stimulating step is carried out by
transmitting at least one impulse of energy to a target location adjacent
to or in close proximity with a carotid sheath of the patient, or to a
target region adjacent to or in close proximity with an auricular branch
of a vagus nerve of the patient.

26. The method of claim 25 wherein the impulse of energy is of a frequency
between about 15 Hz to 50 Hz.

27. The method of claim 25 wherein the impulse of energy is of a frequency
about 25 Hz.

28. The method of claim 25 wherein the impulse of energy is of an
amplitude that may displace particles within the target location, wherein
said energy of said displacement is equivalent to between about 1 to 12
joules per coulomb of displaced charged particles.

29. The method of claim 25 wherein the impulse of energy has a pulsed
on-time of between about 50 to 500 microseconds.

30. The method of claim 25 wherein the impulse of energy has a frequency
of about 25 Hz, a pulsed on-time of about 200-400 microseconds, and an
amplitude that may displace particles within the target location, wherein
said energy of said displacement is equivalent to about 6-12 joules per
coulomb of displaced charged particles.

31. The method of claim 1 wherein energy is transmitted only during a
selected portion of a respiratory cycle of the patient, thereby
counteracting phasic contraction of bronchial smooth muscle.

32. The method of claim 1 wherein energy is transmitted only during a
selected portion of a respiratory cycle of the patient, thereby
modulating the duration of a subsequent phase of respiration.

33. The method of claim 1 wherein power of the transmitted energy is
controlled by the magnitude of a surrogate measurement of the patient's
FEV1, wherein said surrogate measurement is selected from the group
consisting of pulsus paradoxus, accessory muscle use, and airway
resistance.

34. The method of claim 1 wherein a characteristic magnitude of a pulse of
transmitted energy is randomized, wherein said characteristic magnitude
is selected from the group consisting of: power, frequency, amplitude,
duty cycle, pulse width, and pulse shape.

35. The method of claim 34 wherein randomization of the characteristic
magnitude of the pulse of energy occurs at random times.

36. A device for non-invasively treating a medical condition in a patient,
selected from the group of medical conditions consisting of
bronchoconstriction, bronchoconstriction with comorbid hypotension,
bronchoconstriction with comorbid hypertension, bronchoconstriction with
comorbid bradycardia, and bronchoconstriction with comorbid tachycardia,
comprising:a source of power and an energy transmitter, wherein said
source of power supplies energy to said energy transmitter, wherein said
energy transmitter transmits one or more pulses of energy that can
non-invasively stimulate selected nerve fibers in said patient, and
wherein said pulse of energy is selected from the group consisting of
magnetic energy, electrical energy, electromagnetic energy, mechanical
energy, acoustic energy, light energy, and thermal energy.

37. The device of claim 36, wherein the source of power supplies a pulse
of electric charge to a coil and wherein said coil produces a pulse of
magnetic energy when said source of power supplies a pulse of electric
charge to said coil, whereby an electric current and/or an electric field
can be induced by said pulse of magnetic energy, and whereby energy
derived from said induced electric current and/or said induced electric
field can stimulate the selected nerve fibers in the patient.

38. The device of claim 37 further comprising an electrically conducting
medium that encloses essentially all of the coil, wherein said conducting
medium has a shape that conforms to the contour of a target body surface
of the patient when said conducting medium is applied to said target body
surface.

39. The device of claim 38 wherein the target body surface is on a neck of
the patient.

40. The device of claim 37 wherein the coil comprises a toroidal winding
around core material having permeability greater than 10% of the
permeability of Supermendur.

41. The device of claim 37 wherein the coil is cooled by a ferrofluid or
by a magnetorheological fluid or by a mixture of ferrofluid and
magnetorheological fluids.

42. The device of claim 36, wherein pulses of mechanical or acoustic
energy can be transmitted through a target region on a body surface of
the patient.

43. The device of claim 42, wherein the target region is on a surface of
the neck of the patient.

44. The device of claim 42, wherein the pulses of mechanical or acoustic
energy are generated by a linear actuator, an electromagnet, a bimorph, a
piezo crystal, an electrostatic actuator, a speaker coil, crossed
ultrasound beams, or a rotating magnet or mass.

45. The device of claim 36, wherein pulses of light energy or thermal
energy can be transmitted through a target region on a surface of the
patient.

46. The device of claim 45, wherein the target region is on the surface of
an external auditory meatus of the patient.

47. The device of claim 46, wherein light energy or thermal energy is
transmitted successively from a light source to a light modulator to an
earplug and to the target region.

48. The device of claim 45 that contains a source of light having
wavelengths in the range 10.sup.-8 meters to 10.sup.-3 meters, wherein
said source of light comprises: a laser, an incandescent bulb, an arc
lamp, a fluorescent lamp, a light-emitting diode, a super-luminescent
diode, a laser diode, a cathodoluminescent phosphor that is excited by an
electron beam, or a light source that is excited by another light source.

49. The device of claim 48, wherein the source of light has wavelengths in
the infrared region of the electromagnetic spectrum.

50. The device of claim 49, wherein the source of light is a gallium
aluminum arsenide laser or a gallium arsenide laser.

51. The device of claim 45 that contains a light modulator, wherein said
light modulator comprises: a movable variable neutral density filter, a
mechanical light-chopper wheel, a deformable membrane-mirror, an
acousto-optic device, an electro-optic device, a ferroelectric liquid
crystal device, a magneto-optic device, a multiple quantum well device, a
power source that modulates or switches-on/off power to a light source,
rotating crossed polarizers, or a vibrating mirror, diffraction grating,
or hologram.

52. The device of claim 36 that transmits a pulse of electrical energy
through a target region on a surface of the patient via one or more
electrodes and/or electrical leads.

53. The device of claim 52, wherein the target region is on a surface of
the neck of the patient.

54. The device of claim 52, wherein the electrodes and/or electrical leads
have a configuration that may comprise: bipolar, tripolar, concentric
ring, or double concentric ring, wherein said concentric ring or said
double concentric ring configuration may be circular or elliptical.

55. The device of claim 54, wherein the configuration of electrodes and/or
electrical leads focuses the transmitted pulse of electrical energy onto
the selected nerve fibers, without the patient experiencing unpleasant
currents at the target region on the surface of the patient.

56. The device of claim 36 wherein the selected nerve fibers are
associated with a vagus nerve of the patient.

57. The device of claim 36 wherein the pulses of energy have a frequency
of about 15 Hz to 50 Hz.

58. The device of claim 36 wherein the pulses of energy have a frequency
of about 25 Hz.

59. The device of claim 36 wherein the pulse of energy has a pulsed
on-time of between about 50 to 500 microseconds.

60. The device of claim 36 wherein the pulse of energy has a pulsed
on-time of about 200-400 microseconds.

61. The device of claim 36 that can measure the phase of the patient's
respiratory cycle, wherein power of the pulse of energy may vary
depending on the phase of the respiratory cycle.

62. The device of claim 36 wherein power of the pulse of energy may vary
depending on the magnitude of a surrogate measurement of FEV1,
wherein said surrogate measurement is selected from the group consisting
of pulsus paradoxus, accessory muscle use, and airway resistance.

63. The device of claim 36 wherein a characteristic magnitude of the pulse
of energy is randomized, wherein said characteristic magnitude is
selected from the group consisting of: power, frequency, amplitude, duty
cycle, pulse width, and pulse shape.

64. The device of claim 63 wherein the randomization of the characteristic
magnitude of the pulse of energy occurs at random times.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001]This application is a continuation-in-part application of co-pending
U.S. patent application Ser. No. 12/408,131, titled Electrical Treatment
of Bronchial Constriction, filed Mar. 20, 2009, the entire disclosure of
which is hereby incorporated by reference. This application is also
related to commonly assigned co-pending U.S. patent Ser. Nos. 11/555,142,
11/555,170, 11/592,095, 11/591,768, 11/754,522, 11/735,709 and
12/246,605, the complete disclosures of which are incorporated herein by
reference for all purposes.

BACKGROUND OF THE INVENTION

[0002]The field of the present invention relates to the delivery of energy
impulses (and/or fields) to bodily tissues for therapeutic purposes, and
more specifically to non-invasive devices and methods for treating
conditions associated with bronchial constriction. The energy impulses
(and/or fields) comprise electrical and/or magnetic, mechanical and/or
acoustic, and optical and/or thermal energy.

[0003]There are a number of treatments for various infirmities that
require the destruction of otherwise healthy tissue in order to affect a
beneficial effect. Malfunctioning tissue is identified, and then lesioned
or otherwise compromised in order to affect a beneficial outcome, rather
than attempting to repair the tissue to its normal functionality. While
there are a variety of different techniques and mechanisms that have been
designed to focus lesioning directly onto the target nerve tissue,
collateral damage is inevitable.

[0004]Still other treatments for malfunctioning tissue can be medicinal in
nature, in many cases leaving patients to become dependent upon
artificially synthesized chemicals. Examples of this are anti-asthma
drugs such as albuterol, proton pump inhibitors such as omeprazole
(Prilosec), spastic bladder relievers such as Ditropan, and cholesterol
reducing drugs like Lipitor and Zocor. In many cases, these medicinal
approaches have side effects that are either unknown or quite
significant. For example, at least one popular diet pill of the late
1990's was subsequently found to cause heart attacks and strokes.
Unfortunately, the beneficial outcomes of surgery and medicines are,
therefore, often realized at the cost of function of other tissues, or
risks of side effects.

[0005]The use of electrical stimulation for treatment of medical
conditions has been well known in the art for nearly two thousand years.
It has been recognized that electrical stimulation of the brain and/or
the peripheral nervous system and/or direct stimulation of the
malfunctioning tissue, which stimulation is generally a wholly reversible
and non-destructive treatment, holds significant promise for the
treatment of many ailments.

[0006]Electrical stimulation of the brain with implanted electrodes has
been approved for use in the treatment of various conditions, including
pain and movement disorders including essential tremor and Parkinson's
disease. The principle behind these approaches involves disruption and
modulation of hyperactive neuronal circuit transmission at specific sites
in the brain. As compared with the very dangerous lesioning procedures in
which the portions of the brain that are behaving pathologically are
physically destroyed, electrical stimulation is achieved by implanting
electrodes at these sites to, first sense aberrant electrical signals and
then to send electrical pulses to locally disrupt the pathological
neuronal transmission, driving it back into the normal range of activity.
These electrical stimulation procedures, while invasive, are generally
conducted with the patient conscious and a participant in the surgery.

[0007]Brain stimulation, and deep brain stimulation in particular, is not
without some drawbacks. The procedure requires penetrating the skull, and
inserting an electrode into the brain matter using a catheter-shaped
lead, or the like. While monitoring the patient's condition (such as
tremor activity, etc.), the position of the electrode is adjusted to
achieve significant therapeutic potential. Next, adjustments are made to
the electrical stimulus signals, such as frequency, periodicity, voltage,
current, etc., again to achieve therapeutic results. The electrode is
then permanently implanted and wires are directed from the electrode to
the site of a surgically implanted pacemaker. The pacemaker provides the
electrical stimulus signals to the electrode to maintain the therapeutic
effect. While the therapeutic results of deep brain stimulation are
promising, there are significant complications that arise from the
implantation procedure, including stroke induced by damage to surrounding
tissues and the neurovasculature.

[0008]One of the most successful modern applications of this basic
understanding of the relationship between muscle and nerves is the
cardiac pacemaker. Although its roots extend back into the 1800's, it was
not until 1950 that the first practical, albeit external and bulky
pacemaker was developed. Dr. Rune Elqvist developed the first truly
functional, wearable pacemaker in 1957. Shortly thereafter, in 1960, the
first fully implanted pacemaker was developed.

[0009]Around this time, it was also found that the electrical leads could
be connected to the heart through veins, which eliminated the need to
open the chest cavity and attach the lead to the heart wall. In 1975 the
introduction of the lithium-iodide battery prolonged the battery life of
a pacemaker from a few months to more than a decade. The modern pacemaker
can treat a variety of different signaling pathologies in the cardiac
muscle, and can serve as a defibrillator as well (see U.S. Pat. No.
6,738,667 to Deno, et al., the disclosure of which is incorporated herein
by reference).

[0010]Another application of electrical stimulation of nerves has been the
treatment of radiating pain in the lower extremities by means of
stimulation of the sacral nerve roots at the bottom of the spinal cord
(see U.S. Pat. No. 6,871,099 to Whitehurst, et al., the disclosure of
which is incorporated herein by reference).

[0011]Nerve stimulation is thought to be accomplished directly or
indirectly by depolarizing a nerve membrane, causing the discharge of an
action potential; or by hyperpolarization of a nerve membrane, preventing
the discharge of an action potential. Such stimulation may occur after
electrical energy, or also other forms of energy, are transmitted to the
vicinity of a nerve [F. RATTAY. The basic mechanism for the electrical
stimulation of the nervous system. Neuroscience Vol. 89, No. 2, pp.
335-346, 1999; Thomas HEIMBURG and Andrew D. Jackson. On soliton
propagation in biomembranes and nerves. PNAS vol. 102 (no. 28, Jul. 12,
2005): 9790-9795]. Nerve stimulation may be measured directly as an
increase, decrease, or modulation of the activity of nerve fibers, or it
may be inferred from the physiological effects that follow the
transmission of energy to the nerve fibers.

[0012]The present disclosure involves medical procedures that stimulate
nerves by non-invasively transmitting different forms of energy to
nerves. A medical procedure is defined as being non-invasive when no
break in the skin (or other surface of the body, such as a wound bed) is
created through use of the method, and when there is no contact with an
internal body cavity beyond a body orifice (e.g, beyond the mouth or
beyond the external auditory meatus of the ear). Such non-invasive
procedures are distinguished from invasive procedures (including
minimally invasive procedures) in that the invasive procedures insert a
substance or device into or through the skin (or other surface of the
body, such as a wound bed) or into an internal body cavity beyond a body
orifice. The following paragraphs give examples of non-invasive medical
procedures, contrasting some of them with corresponding invasive medical
procedures.

[0013]For example, transcutaneous electrical stimulation of a nerve is
non-invasive because it involves attaching electrodes to the surface of
the skin (or using a form-fitting conductive garment) without breaking
the skin. In contrast, percutaneous electrical stimulation of a nerve is
minimally invasive because it involves the introduction of an electrode
under the skin, via needle-puncture of the skin.

[0014]Another form of non-invasive electrical stimulation, known as
magnetic stimulation, involves the generation (induction) of an eddy
current within tissue, which results from an externally applied
time-varying magnetic field. The principle of operation of magnetic
stimulation, along with a list of medical applications of magnetic
stimulation, is described in: Chris HOVEY and Reza Jalinous, THE GUIDE TO
MAGNETIC STIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,
Carmarthenshire, SA34 0HR, United Kingdom, 2006. As described in that
Guide, applications of magnetic stimulation include the stimulation of
selected peripheral nerves, as well as stimulation of selected portions
of the brain (transcranial magnetic stimulation). Mechanisms underlying
biological effects that result from applying such time-varying magnetic
fields are reviewed in: PILLA, A. A. Mechanisms and therapeutic
applications of time varying and static magnetic fields. In Barnes F and
Greenebaum B (eds), Biological and Medical Aspects of Electromagnetic
Fields. Boca Raton Fla.: CRC Press, 351-411 (2006).

[0015]Diathermy includes non-invasive methods for the heating of tissue,
in which the temperature of tissues is raised by high frequency current,
ultrasonic waves, or microwave radiation originating outside the body.
With shortwave, microwave and radiofrequency diathermy, the tissue to be
treated is irradiated with electromagnetic fields having a carrier
frequency of typically 13.56, 27.12, 40.68, 915 or 2450 MHz, modulated at
frequencies of typically 1 to 7000 Hz. The heating effects may be
dielectric, wherein molecules in tissues try to align themselves with the
rapidly changing electric field, and/or induced, wherein rapidly
reversing magnetic fields induce circulating electric currents and
electric fields in the body tissues, thereby generating heat. With
ultrasound diathermy, high-frequency acoustic vibrations typically in the
range of 800 to 1,000 KHz are used to generate heat in deep tissue.

[0016]Devices similar to those used with diathermy deliver electromagnetic
waves non-invasively to the body for therapeutic purposes, without
explicitly intending to heat tissue. For example, U.S. Pat. No.
4,621,642, entitled Microwave apparatus for physiotherapeutic treatment
of human and animal bodies, to Chen, describes apparatus for performing
acupuncture treatment with microwaves. U.S. Pat. No. 5,131,409, entitled
Device for microwave resonance therapy, to Lobarev et al. discloses the
transmission of an electromagnetic wave that is propagated along a
slotted transmission line in free space toward the patient's skin, for
applications analogous to laser acupuncture. U.S. Pat. No. 7,548,779,
entitled Microwave energy head therapy, to Konchitsky, discloses the
transmission of high frequency electromagnetic pulses non-invasively to a
patient's head, for purposes of treating headaches, epilepsy, and
depression, wherein the brain behaves as an antenna for receiving
electromagnetic energy at certain wavelengths.

[0017]Acupuncture (meridian therapy) may be non-invasive if the
acupuncture tool does not penetrate the skin, as practiced in Toyohari
acupuncture and the pediatric acupuncture style Shonishin. Other forms of
acupuncture may also be non-invasive when they use the Teishein, which is
one of the acupuncture needles described in classical texts of
acupuncture. Even though it is described as an acupuncture needle, the
Teishein does not pierce or puncture the skin. It is used to apply rapid
percussion pressure to the meridian point being treated, so its use may
also be described as a form of acupressure. Electroacupuncture is often
performed as a non-invasive transcutaneous form of electrostimulation.
Laser acupuncture and colorpuncture are also non-invasive in that
acupuncture meridian points are stimulated at the surface of the skin
with light, rather than mechanically or electrically. Although it is
possible to compare the effectiveness of acupuncture treatment with the
effectiveness of Western types of treatments for recognized disorders
such as asthma, it is always possible to ascribe any differences in
effectiveness to differences in mechanisms. This is because acupuncture
treats patients by stimulating acupuncture meridian points, not tissue
such as nerves or blood vessels as identified by modern western medicine.
Furthermore, acupuncture endeavors to produce effects that are not
contemplated by modern western medicine, such as the de qi sensation, and
results using acupuncture may be confounded by the individualized
selection of meridian points, as well as by the simultaneous treatment
with herbal medicines. For example, acupuncture is not considered to be
effective for the treatment of asthma [McCARNEY R W, Brinkhaus B,
Lasserson T J, Linde K. Acupuncture for chronic asthma (Review). The
Cochrane Library 2009, Issue 3. John Wiley & Sons, Ltd.; Michael Y.
SHAPIRA, Neville Berkman, Gila Ben-David, Avraham Avital, Elat Bardach
and Raphael Breuer. Short-term Acupuncture Therapy Is of No Benefit in
Patients With Moderate Persistent Asthma. CHEST 2002; 121:1396-1400; W
GRUBER, E Eber, D Malle-Scheid, A Pfleger, E Weinhandl, L Dorfer, M S
Zach. Laser acupuncture in children and adolescents with exercise induced
asthma. Thorax 2002; 57:222-225], but even if were to have been shown
effective, such effectiveness would, by definition, be attributable only
to the stimulation of meridian points, as interpreted in terms of
theories related to oriental medicine (e.g., restoration of Qi balance in
Traditional Chinese Medicine).

[0019]The mechanical larynx is another example of a non-invasive
mechanical device, which is placed under the mandible so as to produce
vibrations that the patient uses to create speech. Similarly, a hearing
aid directs mechanical vibrations (acoustical or sound vibrations) to the
eardrum. Because it is placed in a natural orifice (the ear canal or
external auditory meatus), the hearing aid is considered to be
non-invasive. Extracorporeal shock wave lithotripsy is another
non-invasive mechanical treatment, which is used to break-up kidney
stones by focusing onto the stones a high-intensity acoustic pulse that
originates from outside the body.

[0020]Imaging procedures that require the insertion of an endoscope or
similar device through the skin or into a cavity beyond a natural orifice
(e.g., bronchoscopy or colonoscopy) are invasive. But capsule endoscopy,
in which a camera having the size and shape of a pill is swallowed, is
non-invasive because the capsule endoscope is swallowed rather than
inserted into a body cavity. Such a swallowed capsule could also be used
to perform non-invasive stimulation of tissue in its vicinity from within
the digestive tract. Similarly, administration of a drug or biologic
through a transdermal patch is non-invasive, whereas administration of a
drug or biologic through a hypodermic needle is invasive. The acts of
taking a drug or biologic orally or through inhalation are not considered
to be medical procedures in the strict sense (so the issue of
invasiveness does not arise), because those acts are functionally
indistinguishable from the normal acts of eating, drinking, or breathing
substances that may be metabolized or otherwise disposed of by the body.

[0021]Radiological procedures, such as X-ray imaging (fluoroscopy),
magnetic resonance imaging and ultrasound imaging, are non-invasive
unless a transducer is inserted into a body cavity or under the skin
(e.g., when an ultrasound transducer is inserted into the patient's
esophagus). However, a non-invasive radiological procedure may be a
component of a larger procedure having invasive components. For example,
a component of the procedure is invasive when the formation of an image
or delivery of energy relies on the presence of a contrast agent,
enhancer, tissue-specific label or radioactive emitter that is inserted
into the patient with a hypodermic needle.

[0022]In the present application, the non-invasive delivery of energy is
intended ultimately to dilate bronchial passages, by relaxing bronchial
smooth muscle. The smooth muscles that line the bronchial passages are
controlled by a confluence of vagus and sympathetic nerve fiber plexuses.
Spasms of the bronchi during asthma attacks and anaphylactic shock can
often be directly related to pathological signaling within these
plexuses. Anaphylactic shock and asthma are major health concerns.

[0023]Asthma, and other airway occluding disorders resulting from
inflammatory responses and inflammation-mediated bronchoconstriction,
affects an estimated eight to thirteen million adults and children in the
United States. A significant subclass of asthmatics suffers from severe
asthma. An estimated 5,000 persons die every year in the United States as
a result of asthma attacks. Up to twenty percent of the populations of
some countries are affected by asthma, estimated at more than a hundred
million people worldwide. Asthma's associated morbidity and mortality are
rising in most countries despite increasing use of anti-asthma drugs.

[0024]Asthma is characterized as a chronic inflammatory condition of the
airways. Typical symptoms are coughing, wheezing, tightness of the chest
and shortness of breath. Asthma is a result of increased sensitivity to
foreign bodies such as pollen, dust mites and cigarette smoke. The body,
in effect, overreacts to the presence of these foreign bodies in the
airways. As part of the asthmatic reaction, an increase in mucous
production is often triggered, exacerbating airway restriction. Smooth
muscle surrounding the airways goes into spasm, resulting in constriction
of airways. The airways also become inflamed. Over time, this
inflammation can lead to scarring of the airways and a further reduction
in airflow. This inflammation leads to the airways becoming more
irritable, which may cause an increase in coughing and increased
susceptibility to asthma episodes.

[0025]Two medicinal strategies exist for treating this problem for
patients with asthma. The condition is typically managed by means of
inhaled medications that are taken after the onset of symptoms, or by
injected and/or oral medication that are taken chronically. The
medications typically fall into two categories; those that treat the
inflammation, and those that treat the smooth muscle constriction. The
first is to provide anti-inflammatory medications, like steroids, to
treat the airway tissue, reducing its tendency to over-release the
molecules that mediate the inflammatory process. The second strategy is
to provide a smooth muscle relaxant (e.g. an anticholinergic) to reduce
the ability of the muscles to constrict.

[0026]It has been highly preferred that patients rely on avoidance of
triggers and anti-inflammatory medications, rather than on the
bronchodilators as their first line of treatment. For some patients,
however, these medications, and even the bronchodilators are insufficient
to stop the constriction of their bronchial passages, and more than five
thousand people suffocate and die every year as a result of asthma
attacks.

[0027]Anaphylaxis likely ranks among the other airway occluding disorders
of this type as the most deadly, claiming many deaths in the United
States every year. Anaphylaxis (the most severe form of which is
anaphylactic shock) is a severe and rapid systemic allergic reaction to
an allergen. Minute amounts of allergens may cause a life-threatening
anaphylactic reaction. Anaphylaxis may occur after ingestion, inhalation,
skin contact or injection of an allergen. Anaphylactic shock usually
results in death in minutes if untreated. Anaphylactic shock is a
lifethreatening medical emergency because of rapid constriction of the
airway. Brain damage sets in quickly without oxygen.

[0028]The triggers for these fatal reactions range from foods (nuts and
shellfish), to insect stings (bees), to medication (radio contrasts and
antibiotics). It is estimated that 1.3 to 13 million people in the United
States are allergic to venom associated with insect bites; 27 million are
allergic to antibiotics; and 5-8 million suffer food allergies. All of
these individuals are at risk of anaphylactic shock from exposure to any
of the foregoing allergens. In addition, anaphylactic shock can be
brought on by exercise. Yet all are mediated by a series of
hypersensitivity responses that result in uncontrollable airway occlusion
driven by smooth muscle constriction, and dramatic hypotension that leads
to shock. Cardiovascular failure, multiple organ ischemia, and
asphyxiation are the most dangerous consequences of anaphylaxis.

[0029]Anaphylactic shock requires advanced medical care immediately.
Current emergency measures include rescue breathing; administration of
epinephrine; and/or intubation if possible. Rescue breathing may be
hindered by the closing airway but can help if the victim stops breathing
on his own. Clinical treatment typically consists of antihistamines
(which inhibit the effects of histamine at histamine receptors) which are
usually not sufficient in anaphylaxis, and high doses of intravenous
corticosteroids. Hypotension is treated with intravenous fluids and
sometimes vasoconstrictor drugs. For bronchospasm, bronchodilator drugs
such as salbutamol are employed.

[0030]Given the common mediators of both asthmatic and anaphylactic
bronchoconstriction, it is not surprising that asthma sufferers are at a
particular risk for anaphylaxis. Still, estimates place the numbers of
people who are susceptible to such responses at more than 40 million in
the United States alone.

[0031]Tragically, many of these patients are fully aware of the severity
of their condition, and die while struggling in vain to manage the attack
medically. Many of these incidents occur in hospitals or in ambulances,
in the presence of highly trained medical personnel who are powerless to
break the cycle of inflammation and bronchoconstriction (and
life-threatening hypotension in the case of anaphylaxis) affecting their
patient.

[0032]Unfortunately, prompt medical attention for anaphylactic shock and
asthma are not always available. For example, epinephrine is not always
available for immediate injection. Even in cases where medication and
attention is available, life saving measures are often frustrated because
of the nature of the symptoms. Constriction of the airways frustrates
resuscitation efforts, and intubation may be impossible because of
swelling of tissues.

[0033]Typically, the severity and rapid onset of anaphylactic reactions
does not render the pathology amenable to chronic treatment, but requires
more immediately acting medications. Among the most popular medications
for treating anaphylaxis is epinephrine, commonly marketed in so-called
"Epipen" formulations and administering devices, which potential
sufferers carry with them at all times. In addition to serving as an
extreme bronchodilator, epinephrine raises the patient's heart rate
dramatically in order to offset the hypotension that accompanies many
reactions. This cardiovascular stress can result in tachycardia, heart
attacks and strokes.

[0034]Chronic obstructive pulmonary disease (COPD) is a major cause of
disability, and is the fourth leading cause of death in the United
States. More than 12 million people are currently diagnosed with COPD. An
additional 12 million likely have the disease and don't even know it.
COPD is a progressive disease that makes it hard for the patient to
breathe. COPD can cause coughing that produces large amounts of mucus,
wheezing, shortness of breath, chest tightness and other symptoms.
Cigarette smoking is the leading cause of COPD, although longterm
exposure to other lung irritants, such as air pollution, chemical fumes
or dust may also contribute to COPD. In COPD, less air flows in and out
of the bronchial airways for a variety of reasons, including loss of
elasticity in the airways and/or air sacs, inflammation and/or
destruction of the walls between many of the air sacs and overproduction
of mucus within the airways.

[0035]The term COPD includes two primary conditions: emphysema and chronic
obstructive bronchitis. In emphysema, the walls between many of the air
sacs are damaged, causing them to lose their shape and become floppy.
This damage also can destroy the walls of the air sacs, leading to fewer
and larger air sacs instead of many tiny ones. In chronic obstructive
bronchitis, the patient suffers from permanently irritated and inflamed
bronchial tissue that is slowly and progressively dying. This causes the
lining to thicken and form thick mucus, making it hard to breathe. Many
of these patients also experience periodic episodes of acute airway
reactivity (i.e., acute exacerbations), wherein the smooth muscle
surrounding the airways goes into spasm, resulting in further
constriction and inflammation of the airways. Acute exacerbations occur,
on average, between two and three times a year in patients with moderate
to severe COPD and are the most common cause of hospitalization in these
patients (mortality rates are 11%). Frequent acute exacerbations of COPD
cause lung function to deteriorate quickly, and patients never recover to
the condition they were in before the last exacerbation. Similar to
asthma, current medical management of these acute exacerbations is often
insufficient.

[0036]Unlike cardiac arrhythmias, which can be treated chronically with
pacemaker technology, or in emergent situations with equipment like
defibrillators (implantable and external), there is virtually no
commercially available medical equipment that can chronically reduce the
baseline sensitivity of the smooth muscle tissue in the airways to reduce
the predisposition to asthma attacks, reduce the symptoms of COPD or to
break the cycle of bronchial constriction associated with an acute asthma
attack or anaphylaxis.

[0037]Therefore, there is a need in the art for new products and methods
for treating the immediate symptoms of bronchial constriction resulting
from pathologies such as anaphylactic shock, asthma and COPD. In
particular, there is a need in the art for non-invasive devices and
methods to treat the immediate symptoms of bronchial constriction.
Potential advantages of such non-invasive medical methods and devices
relative to comparable invasive procedures are as follows. The patient
may be more psychologically prepared to experience a procedure that is
non-invasive and may therefore be more cooperative, resulting in a better
outcome. Non-invasive procedures may avoid damage of biological tissues,
such as that due to bleeding, infection, skin or internal organ injury,
blood vessel injury, and vein or lung blood clotting. Non-invasive
procedures are generally painless and may be performed without the need
for even local anesthesia. Less training may be required for use of
non-invasive procedures by medical professionals. In view of the reduced
risk ordinarily associated with non-invasive procedures, some such
procedures may be suitable for use by the patient or family members at
home or by first-responders at home or at a workplace, and the cost of
non-invasive procedures may be reduced relative to comparable invasive
procedures.

SUMMARY OF THE INVENTION

[0038]The present invention involves products and methods for the
treatment of asthma, COPD, anaphylaxis, and other pathologies involving
the constriction of the primary airways, utilizing an energy source
(comprising electrical and/or magnetic, mechanical and/or acoustic, and
optical and/or thermal energy), that may be transmitted non-invasively
to, or in close proximity to, a selected nerve to temporarily stimulate,
block and/or modulate the signals in the selected nerve. The present
invention is particularly useful for the acute relief of symptoms
associated with bronchial constriction, i.e., asthma attacks, COPD
exacerbations and/or anaphylactic reactions. The teachings of the present
invention provide an emergency response to such acute symptoms, by
producing immediate airway dilation and/or heart function increase to
enable subsequent adjunctive measures (such as the administration of
epinephrine) to be effectively employed.

[0039]In one aspect of the present invention, a method of treating
bronchial constriction comprises stimulating selected nerve fibers
responsible for reducing the magnitude of constriction of smooth
bronchial muscle to increase the activity of the selected nerve fibers.

[0040]In a preferred embodiment, the selected nerve fibers comprise those
that send a parasympathetic, afferent vagal signal to the brain, which
then triggers an efferent sympathetic signal to stimulate the release of
catecholamines (comprising endogenous beta-agonists, epinephrine and/or
norepinephrine) from the adrenal glands and/or from nerve endings that
are distributed throughout the body. In yet other embodiments, the method
includes stimulating, inhibiting, blocking or otherwise modulating other
nerves that release systemic bronchodilators or nerves that directly
modulate parasympathetic ganglia transmission (by stimulation or
inhibition of preganglionic to postganglionic transmissions). In an
alternative embodiment, the fibers responsible for bronchodilation are
interneurons that are completely contained within the walls of the
bronchial airways. These interneurons are responsible for modulating the
cholinergic nerves in the bronchial passages. In this embodiment, the
increased activity of the interneurons will cause inhibition or blocking
of the cholinergic nerves responsible for bronchial constriction, thereby
facilitating opening of the airways.

[0041]The stimulating step is preferably carried out without substantially
stimulating excitatory nerve fibers, such as parasympathetic cholinergic
nerve fibers, that are responsible for increasing the magnitude of
constriction of smooth muscle. In this manner, the activity of the nerve
fibers responsible for bronchodilation are increased without increasing
the activity of the cholinergic fibers which would otherwise induce
further constriction of the smooth muscle. Alternatively, the method may
comprise the step of actually inhibiting or blocking these cholinergic
nerve fibers such that the nerves responsible for bronchodilation are
stimulated while the nerves responsible for bronchial constriction are
inhibited or completely blocked. This blocking/inhibiting signal may be
separately applied to the inhibitory nerves; or it may be part of the
same signal that is applied to the nerve fibers responsible for
bronchodilation.

[0042]In an alternative embodiment, a method of treating bronchial
constriction comprises stimulating, inhibiting, blocking or otherwise
modulating selected efferent sympathetic nerves responsible for mediating
bronchial passages either directly or indirectly. The selected efferent
sympathetic nerves may be nerves that directly innervate the bronchial
smooth muscles. It has been postulated that asthma patients typically
have more sympathetic nerves that directly innervate the bronchial smooth
muscle than individuals that do not suffer from asthma.

[0043]In another aspect of the invention, a method of treating bronchial
constriction includes applying an energy impulse to a target region in
the patient and acutely reducing the magnitude of bronchial constriction
in the patient. The energy impulse is transmitted non-invasively from an
energy source, comprising electrical and/or magnetic, mechanical and/or
acoustic, and optical and/or thermal sources of energy. As used herein,
the term acutely means that the energy impulse immediately begins to
interact with one or more nerves to produce a response in the patient.
The energy impulse is preferably sufficient to promptly and
quantitatively ameliorate a symptom, for example, to increase the Forced
Expiratory Volume in 1 second (FEV1) of the patient by a clinically
significant amount in a period of time less than about 6 hours,
preferably less than 3 hours and more preferably less than 90 minutes and
even more preferably less that 15 minutes. A clinically significant
amount is defined herein as at least a 12% increase in the patient's
FEV1 versus the FEV1 measured prior to application of the
energy impulse. In an exemplary embodiment, the energy impulse is
sufficient to increase the FEV1 by at least 19% over the FEV1
as predicted.

[0044]In another aspect of the invention, a method for treating bronchial
constriction comprises applying one or more energy impulse(s) of a
frequency of about 15 Hz to 50 Hz to a selected region within a patient
to reduce a magnitude of constriction of bronchial smooth muscle. In a
preferred embodiment, the method includes positioning the coil of a
magnetic stimulator non-invasively on or above a patient's neck and
applying a magnetically-induced electrical impulse non-invasively to the
target region within the neck to stimulate, inhibit or otherwise modulate
selected nerve fibers that interact with bronchial smooth muscle.
Preferably, the target region is adjacent to, or in close proximity with,
the carotid sheath.

[0045]In one embodiment of the present invention, the source of
stimulation energy is a magnetic stimulator that preferably operates to
induce an electrical signal within the tissue, where the induced
electrical signal has a frequency between about 1 Hz to 3000 Hz, a pulse
duration of between about 10-1000 microseconds, and an amplitude of
between about 1-20 volts. The induced electrical signal may be one or
more of: a full or partial sinusoid, a square wave, a rectangular wave,
and triangle wave. By way of example, the at least one induced electrical
signal may be of a frequency between about 15 Hz to 35 Hz. By way of
example, at least one induced electrical signal may have a pulsed on-time
of between about 50 to 1000 microseconds, such as between about 100 to
300 microseconds, or about 200 microseconds. By way of example, the at
least one induced electrical signal may have an amplitude of about 5-15
volts, such as about 12 volts.

[0046]Applicant has made the unexpected discovered that applying an
electrical impulse to a selected region of a patient's neck within this
particular frequency range results in almost immediate and significant
improvement in bronchodilation, as discussed in further detail below.
Applicant has further discovered that applying electrical impulses
outside of the selected frequency range (15 Hz to 50 Hz) does not result
in significant improvement and, in some cases, may worsen the patient's
bronchoconstriction. Preferably, the frequency is about 25 Hz. In this
embodiment, the electrical impulse(s) have an amplitude between about 0.5
to 12 volts and have a pulsed on-time of between about 50 to 500
microseconds, preferably about 200-400 microseconds. The preferred
voltage will depend on the size and shape of the apparatus used to
deliver the electrical impulse and the distance between that apparatus
and the target nerves. In certain embodiments the electrical impulse
preferably has an amplitude of at least 6 volts and more preferably
between about 7-12 volts. In other embodiments the amplitude is
preferably lower, i.e., less than 6 volts and more preferably between
about 0.1 to 2 volts.

[0047]The energy impulse(s) are applied in a manner that reduces the
constriction of the smooth muscle lining the bronchial passages to
relieve the spasms that occur during anaphylactic shock, acute
exacerbations of COPD or asthma attacks. In some embodiments, the
mechanisms by which the appropriate impulse is applied to the selected
region within the patient include positioning a magnetic stimulator coil
non-invasively on or above the patient's neck in the vicinity of the
nervous tissue controlling the pulmonary and/or cardiac muscles, which
coil is coupled to an external magnetic impulse/eddy-current generating
device. The electric field and/or eddy-currents induced by the coil of
the magnetic stimulator creates a field of effect that permeates the
target nerve fibers and causes the stimulating, blocking and/or
modulation of signals to the subject smooth muscles, and/or the blocking
and/or affecting of histamine response. It shall be understood that
leadless impulses as shown in the art may be utilized for applying
impulses to the target regions.

[0048]In other embodiments, a magnetic stimulator coil is positioned
non-invasively on or above an anatomical location other than the
patient's neck, in the vicinity of nervous tissue controlling
bronchodilation, which coil is coupled to an external magnetic-field
impulse/eddy-current impulse generating device. The electromagnetic field
and/or eddy-currents induced as energy impulses by the coil of the
magnetic stimulator create a field of effect that permeates the target
nerve fibers and cause the stimulating, blocking, and/or modulation of
signals to the subject smooth muscles, and/or the blocking and/or
affecting of histamine response.

[0049]In other embodiments, the mechanisms by which the appropriate energy
impulse is applied to the selected region within the patient comprise
positioning a mechanical or acoustical vibrator (or
mechanical-vibration/sound conducting form-fitting garment)
non-invasively, on or above the patient's neck, on or above the patient's
ear or ear-canal orifice, or on or above some other anatomical location
in the vicinity of nervous tissue controlling bronchodilation, which
mechanical or acoustical vibrator is coupled to an external
mechanical-impulse or sound-impulse generating device. The mechanical or
acoustical vibrations transmitted non-invasively by the vibrator creates
a field of effect that permeates the target nerve fibers and cause the
stimulating, blocking, and/or modulation of signals to the subject smooth
muscles, and/or the blocking and/or affecting of histamine response.

[0050]In other embodiments, the mechanisms by which the appropriate energy
impulse is applied to the selected region within the patient comprise
positioning a light or heat emitting device (or a light-conducting or
heat-conducting form-fitting garment) non-invasively, on or above the
patient's ear or ear-canal orifice, or on or above some other anatomical
location in the vicinity of nervous tissue controlling bronchodilation,
which light or heat emitting device is coupled to an external light or
heat generating source, said source being a device that can generate
light or heat as impulses of energy corresponding to electromagnetic
radiation having wavelengths in the infra-red, far-infrared, visible, or
ultra-violet ranges of electromagnetic radiation (having wavelengths in
the range 10-8 meters to 10-3 meters, inclusive). The light or heat
transmitted non-invasively from the light or heat emitting device creates
a field of effect that permeates the target nerve fibers and cause the
stimulating, blocking, and/or modulation of signals to the subject smooth
muscles, and/or the blocking and/or affecting of histamine response.

[0051]In other embodiments, the mechanisms by which the appropriate energy
impulse is applied to the selected region within the patient comprise
positioning the distal ends of one or more electrical lead (or
electrically conducting form-fitting garment) non-invasively, on or above
the patient's neck, on or above the patient's ear or ear-canal orifice,
or on or above some other anatomical location in the vicinity of nervous
tissue controlling bronchodilation, which lead or leads are coupled to an
external electrical impulse generating device, for example via an
electrode. The electric field generated non-invasively at the distal tip
of the lead creates a field of effect that permeates the target nerve
fibers and cause the stimulating, blocking, and/or modulation of signals
to the subject smooth muscles, and/or the blocking and/or affecting of
histamine response.

[0052]The novel systems, devices and methods for treating bronchial
constriction are more completely described in the following detailed
description of the invention, with reference to the drawings provided
herewith, and in claims appended hereto. Other aspects, features,
advantages, etc. will become apparent to one skilled in the art when the
description of the invention herein is taken in conjunction with the
accompanying drawings.

INCORPORATION BY REFERENCE

[0053]Hereby, all issued patents, published patent applications, and
non-patent publications that are mentioned in this specification are
herein incorporated by reference in their entirety for all purposes, to
the same extent as if each individual issued patent, published patent
application, or non-patent publication were specifically and individually
indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0054]For the purposes of illustrating the various aspects of the
invention, there are shown in the drawings forms that are presently
preferred, it being understood, however, that the invention is not
limited by or to the precise data, methodologies, arrangements and
instrumentalities shown, but rather only by the claims.

[0055]FIG. 1 is a schematic view of a nerve modulating device according to
the present invention, which supplies controlled pulses of electrical
current to a magnetic stimulator coil.

[0056]FIG. 2 illustrates an exemplary electrical voltage/current profile
for a blocking and/or modulating impulse applied to a portion or portions
of a nerve in accordance with an embodiment of the present invention.

[0057]FIG. 3 is a schematic view of an alternate embodiment of a nerve
modulating device according to the present invention, which supplies
controlled pulses of electrical current to a linear actuator that is used
as a mechanical vibrator.

[0058]FIG. 4 is a schematic view of an alternate embodiment of a nerve
modulating device according to the present invention, which controls the
emission of pulses of light from an earplug.

[0061]FIGS. 19-24 graphically illustrate the inability of signals taught
by U.S. patent application Ser. No. 10/990,938 to achieve the results of
the present invention; and

[0062]FIGS. 25 and 26 graphically illustrates the inability of signals
taught by International Patent Application Publication Number WO 93/01862
to achieve the results of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063]In the present invention, energy is transmitted non-invasively to a
patient. Transmission of energy is defined herein to mean the macroscopic
transfer of energy from one point to another point through a medium,
including possibly a medium that is free space, such that in going from a
point of origin to a point of destination, the energy is transferred
successively to the medium at points along a path connecting the points
of origin and destination. Some energy at the point of origin will
ordinarily be lost to the medium before arriving at the point of
destination. If energy is radiated in all directions from the point of
origin, then only that energy following a path from the point of origin
to the destination point is considered to be transmitted. According to
this definition, electrical, magnetic, electromagnetic, mechanical,
acoustical, and thermal energy may be transmitted. But chemical energy in
the form of chemical bonds would ordinarily not fall under this
definition of energy transmission, because when moving macroscopically
between two points, e.g., by diffusion, the energy contained within
chemical bonds would not ordinarily be transferred to a medium at
intervening points. Thus, the diffusion of chemical substances would
ordinarily be considered to be a flux of mass (kgm-2s-1) rather than a
flux of energy (Jm-2s-1).

[0064]One aspect of the present invention teaches non-invasive methods for
treating bronchial constriction by stimulating selected nerve fibers that
are responsible for reducing the magnitude of constriction of smooth
bronchial muscle, such that the activity of those selected nerve fibers
is increased and smooth bronchial muscle is dilated. Prominent among such
nerve fibers are some that are associated with the vagus nerve.

[0065]As described below in connection with different embodiments of the
present invention, non-invasive methods involving the transmission of
magnetic and/or electrical energy as well as mechanical and/or acoustic
energy have been used to stimulate nerves that could be responsible for
bronchodilation, particularly the vagus nerve. However, to the knowledge
of the present applicants, they have never been performed in such a way
as to achieve bronchodilation. Conversely, energy has been applied to
patients in such a way as to bring about bronchodilation, but those
applications involve methods that are invasive, not non-invasive. For
example, U.S. Pat. No. 7,740,017, entitled Method for treating an asthma
attack, to Danek et al., discloses an invasive method for directing radio
frequency energy to the lungs to bring about bronchodilation. U.S. Pat.
No. 7,264,002, entitled Methods of treating reversible obstructive
pulmonary disease, to Danek et al., discloses methods of treating an
asthmatic lung invasively, by advancing a treatment device into the lung
and applying energy. Those invasive methods attempt to dilate the bronchi
directly, rather than to stimulate nerve fibers that in turn bring about
bronchodilation. However, our own experiments, which are described below,
demonstrate that minimally invasive electrical stimulation of nerve
fibers can in fact achieve bronchodilation. They motivate the present
application that discloses several methods and devices to stimulate such
nerve fibers non-invasively, in order to produce bronchodilation.

[0066]In the preferred embodiments, a time-varying magnetic field
originating outside of a patient is applied to a patient, such that the
magnetic field generates an electromagnetic field and/or induces eddy
currents within tissue of the patient. The invention is particularly
useful for inducing applied electrical impulses that interact with the
signals of one or more nerves, or muscles, to achieve a therapeutic
result, such as relaxation of the smooth muscle of the bronchia. In
particular, the present invention provides methods and devices for
immediate relief of acute symptoms associated with bronchial constriction
such as asthma attacks, COPD exacerbations and/or anaphylactic reactions.

[0067]For convenience, much of the remaining disclosure will be directed
specifically to treatment in or around the carotid sheath with devices
positioned non-invasively on or near a patient's neck, but it will be
appreciated that the systems and methods of the present invention can be
applied equally well to other tissues and nerves of the body, including
but not limited to other parasympathetic nerves, sympathetic nerves,
spinal or cranial nerves. In addition, the present invention can be used
to directly or indirectly stimulate or otherwise modulate nerves that
innervate bronchial smooth muscle. While the exact physiological causes
of asthma, COPD and anaphylaxis have not been determined, the present
invention postulates that the direct mediation of the smooth muscles of
the bronchia is the result of activity in one or more nerves near or in
the carotid sheath. In the case of asthma, it appears that the airway
tissue has both (i) a hypersensitivity to the allergen that causes the
overproduction of the cytokines that stimulate the cholinergic receptors
of the nerves and/or (ii) a baseline high parasympathetic tone or a high
ramp up to a strong parasympathetic tone when confronted with any level
of cholenergic cytokine. The combination can be lethal. Anaphylaxis
appears to be mediated predominantly by the hypersensitivity to an
allergen causing the massive overproduction of cholenergic receptor
activating cytokines that overdrive the otherwise normally operating
vagus nerve to signal massive constriction of the airways. Drugs such as
epinephrine drive heart rate up while also relaxing the bronchial
muscles, effecting temporary relief of symptoms from these conditions.
Experience has shown that severing the vagus nerve (an extreme version of
reducing the parasympathetic tone) has an effect similar to that of
epinephrine on heart rate and bronchial diameter in that the heart begins
to race (tachycardia) and the bronchial passageways dilate. One aspect of
the present invention is that it may produce an effect similar to that of
epinephrine in relaxing the contraction of smooth muscle in bronchial
passageways. However, the present invention is not intended to reverse
hypersensitivity to an allergen or to modulate the production of
cytokines.

[0068]To investigate the mechanism by which vagal (or vagus) nerve
stimulation (VNS) can result in bronchodilation, the present applicant
and colleagues performed experiments that are reported herein [published
as conference proceedings: Bruce J. SIMON, Charles W. Emala, Lawrence M.
Lewis, Daniel Theodoro, Yanina Purim-Shem-Tov, Pedro Sepulveda, Thomas J.
Hoffmann, Peter Staats. Vagal Nerve Stimulation for Relief of
Bronchoconstriction: Preliminary Clinical Data and Mechanism of Action.
Proceedings page 119 of Neuromodulation: 2010 and Beyond; North American
Neuromodulation Society 13th Annual Meeting, Dec. 3-6, 2009]. The
experiments are described in detail later in the present application, but
the following is a summary of their design, results, and interpretation.

[0069]Animal studies were first performed. Under IACUC approved protocols,
male Hartley guinea pigs were anesthetized with i.p. urethane and
ventilated through a tracheostomy. Bronchoconstriction was induced via iv
histamine or acetylcholine with or without simultaneous, bilateral VNS at
25 Hz, 200 ms, 1-3 V. Selective antagonists (L-NAME/iNANC,
propranolol/sympathetic) and vagal ligation were used to elucidate the
neural pathways responsible for the bronchodilation response. The results
of these animal studies were as follows. Ligating both vagus nerves
caudal to the stimulating electrodes did not block the VNS-mediated
attenuation of bronchoconstriction while ligating rostrally did block the
attenuation of bronchoconstriction. This suggests that the mechanism was
mediated through an afferent neural pathway. Blockade of nitric oxide
synthesis by pretreatment with L-NAME (a primary mediator of inhibitory
non-adrenergic, non-cholinergic (iNANC) bronchodilator pathways) had no
effect on VNS-mediated attenuation of bronchoconstriction while
pretreatment with propranolol reversibly blocked the effect.

[0070]Human studies were also performed. Under an FDA IDE with IRB
approval, six adult patients were studied who were seen in the emergency
department for moderate to severe asthma (FEV1 16%-69%) and who failed to
respond to conventional pharmacologic therapy, including
β2-adrenergic receptor agonists (6/6) and oral steroid treatment
(5/6). Following consent, patients were prepped, draped, and using only
local anesthesia, underwent percutaneous placement of an electrode lead
in the vicinity of the carotid sheath, assisted by ultrasound guidance.
Treatment consisted of up to 180 minutes of continuous electrical
stimulation at 25 Hz, 200 ms, 1-12 V. Benefit was determined by changes
in FEV1. The results of these clinical studies were as follows. Within 30
minutes of VNS therapy, the mean % predicted FEV1 increased from
49.8±7.8 to 58.8±7.5 (p=0.003). FEV1 continued to improve during
treatment (mean maximum increase of ˜44%) and benefit remained
after treatment ended (at 30 minutes post, % predicted FEV1 was
67.1±8.1, p=0.004). There were no episodes of hypotension,
bradycardia, diaphoresis, or increased tachycardia during stimulation,
nor complications within the one week follow-up.

[0071]We therefore conclude the following from the animal and clinical
studies. Preliminary data suggests that VNS can safely induce significant
bronchodilation in humans during an exacerbation of asthma in those who
with a poor response to standard pharmacological treatment. Preliminary
animal data indicates that VNS activates afferent nerves and may act
through a sympathetic reflex pathway to mediate bronchodilation. Thus, we
found that bronchodilation resulting from stimulation of the vagus nerve
works by causing the systemic release of the natural, endogenous
β-agonists, epinephrine and norepinephrine. These catecholamines can
reach the constricted bronchial smooth muscle through an internal,
systemic pathway, thereby overcoming any potential problems with inhaled
β-agonists, for example, due to mucus congestion. The electrical
field delivered to the vagus nerve was optimized to stimulate the release
of these hormones into the circulation at concentrations that produce
bronchial smooth muscle relaxation, but have little effect on heart rate
or blood pressure. The data suggest that the release of these
catecholamines is mediated by a parasympathetic, afferent vagal signal to
the brain, which then triggers an efferent sympathetic signal to
stimulate the release of catecholamines from the adrenal glands. These
animal data show that the stimulator is effective even if the vagus nerve
is tied off distal to the electrode and that the bronchodilation effect
can be blocked with the β-blocker propranolol. In addition,
stimulation was found to be ineffective in animals that have had their
adrenal glands removed.

[0072]In accordance with the present invention, the delivery, in a patient
suffering from severe asthma, COPD or anaphylactic shock, of an impulse
of energy sufficient to stimulate, block and/or modulate transmission of
signals of selected nerve fibers will result in relaxation of the bronchi
smooth muscle, dilating airways and/or counteract the effect of histamine
on the vagus nerve. Depending on the placement of the impulse, the
stimulating, blocking and/or modulating signal can also raise the heart
function.

[0073]Stimulating, blocking and/or modulating the signal in selected
nerves to reduce parasympathetic tone provides an immediate emergency
response, much like a defibrillator, in situations of severe asthma or
COPD attacks or anaphylactic shock, providing immediate temporary
dilation of the airways and optionally an increase of heart function
until subsequent measures, such as administration of epinephrine, rescue
breathing and intubation can be employed. Moreover, the teachings of the
present invention permit immediate airway dilation and/or heart function
increase to enable subsequent life saving measures that otherwise would
be ineffective or impossible due to severe constriction or other
physiological effects. Treatment in accordance with the present invention
provides bronchodilation and optionally increased heart function for a
long enough period of time so that administered medication such as
epinephrine has time to take effect before the patient suffocates.

[0074]In a preferred embodiment, a method of treating bronchial
constriction comprises stimulating selected nerve fibers responsible for
reducing the magnitude of constriction of smooth bronchial muscle to
increase the activity of the selected nerve fibers. Certain signals of
the parasympathetic nerve fibers cause a constriction of the smooth
muscle surrounding the bronchial passages, while other signals of the
parasympathetic nerve fibers carry the opposing signals that tend to open
the bronchial passages. Specifically, it should be recognized that
certain signals, such as cholinergic fibers mediate a response similar to
that of histamine, while other signals generate an effect similar to
epinephrine. [CANNING, Brendan J. Reflex regulation of airway smooth
muscle tone. J Appl Physiol 101: 971-985, 2006.] As described in
connection with our experiments summarized above, the latter fibers
include those that may directly or indirectly cause the systemic release
of catecholamines from the adrenal glands and/or from nerve endings
distributed throughout the body, so in what follows, those latter fibers
will be called collectively "epinephrine-like-effect" fibers. Repeated
stimulation of some such fibers may cause the repeated pulsatile systemic
release of epinephrine (and/or other catecholamies), leading eventually
to circulating steady state concentrations of catecholamines that are
determined by the stimulation frequency as well as the half-life of
circulating catecholamines. Given the postulated balance between these
signals, stimulating the "epinephrine-like-effect" nerve fibers and/or
blocking or removing the cholinergic signals should create an imbalance
emphasizing bronchodilation.

[0075]In one embodiment of the present invention, the selected nerve
fibers are "epinephrine-like-effect" nerve fibers which are generally
responsible for bronchodilation. Stimulation of these
"epinephrine-like-effect" fibers increases their activity, thereby
increasing bronchodilation and facilitating opening of the airways of the
mammal. The stimulation may occur through direct stimulation of the
efferent "epinephrine-like-effect" fibers that cause bronchodilation or
indirectly through stimulation of the afferent sympathetic or
parasympathetic nerves which carry signals to the brain and then back
down through the "epinephrine-like-effect" nerve fibers to the bronchial
passages.

[0076]In certain embodiments, the "epinephrine-like-effect" nerve fibers
are associated with the vagus nerve and are thus directly responsible for
bronchodilation. Alternatively, the "epinephrine-like-effect" fibers may
be interneurons that are completely contained within the walls of the
bronchial airways. These interneurons are responsible for modulating the
cholinergic nerves in the bronchial passages. In this embodiment, the
increased activity of the "epinephrine-like-effect" interneurons will
cause inhibition or blocking of the cholinergic nerves responsible for
bronchial constriction, thereby facilitating opening of the airways.

[0077]As discussed above, certain parasympathetic signals mediate a
response similar to histamine, thereby causing a constriction of the
smooth muscle surrounding the bronchial passages. Accordingly, the
stimulating step of the present invention is preferably carried out
without substantially stimulating the parasympathetic nerve fibers, such
as the cholinergic nerve fibers associated with the vagus nerve, that are
responsible for increasing the magnitude of constriction of smooth
muscle. In this manner, the activity of the "epinephrine-like-effect"
nerve fibers are increased without increasing the activity of the
adrenergic fibers which would otherwise induce further constriction of
the smooth muscle. Alternatively, the method may comprise the step of
actually inhibiting or blocking these cholinergic nerve fibers such that
the nerves responsible for bronchodilation are stimulated while the
nerves responsible for bronchial constriction are inhibited or completely
blocked. This blocking signal may be separately applied to the inhibitory
nerves; or it may be part of the same signal that is applied to the
"epinephrine-like-effect" nerve fibers.

[0078]While it is believed that there are little to no direct sympathetic
innervations of the bronchial smooth muscle in most individuals, recent
evidence has suggested asthma patients do have such sympathetic
innervations within the bronchial smooth muscle. In addition, the
sympathetic nerves may have an indirect effect on the bronchial smooth
muscle.

[0080]Method and devices of the present invention are particularly useful
for providing substantially immediate relief of acute symptoms associated
with bronchial constriction such as asthma attacks, COPD exacerbations
and/or anaphylactic reactions. One of the key advantages of the present
invention is the ability to provide almost immediate dilation of the
bronchial smooth muscle in patients suffering from acute
bronchoconstriction, opening the patient's airways and allowing them to
breathe and more quickly recover from an acute episode (i.e., a
relatively rapid onset of symptoms that are typically not prolonged or
chronic).

[0081]The magnitude of bronchial constriction in a patient is typically
expressed in a measurement referred to as the Forced Expiratory Volume in
1 second (FEV1). FEV1 represents the amount of air a patient
exhales (expressed in liters) in the first second of a pulmonary function
test, which is typically performed with a spirometer. The spirometer
compares the FEV1 result to a standard for the patient, which is
based on the predicted value for the patient's weight, height, sex, age
and race. This comparison is then expressed as a percentage of the
FEV1 as predicted. Thus, if the volume of air exhaled by a patient
in the first second is 60% of the predicted value based on the standard,
the FEV1 will be expressed in both the actual liters exhaled and as
a percentage of predicted (i.e., 60% of predicted). In practice, a
baseline value of FEV1 is measured, and after a therapeutic intervention,
a second value of FEV1 is measured in order to ascertain the efficacy of
the intervention. It should be noted that interventions known to dilate
the bronchi (e.g., administration of epinephrine or the teachings of the
present invention) are most likely to succeed when the patient's baseline
FEV1 value is in the range -1 to -5 standard deviations of the
statistical distribution of values of FEV1 for individuals in the
population at large. This is because if the baseline value is outside
that range, the patient's breathing problem is less likely to be due to
bronchoconstriction and more likely to be due to something else, such as
inflammatory mechanisms.

[0082]Certain other measurements may act as surrogates for the measurement
of FEV1. Those other non-invasive measurements are particularly
useful for patients who cannot cooperate to perform measurements made by
spirometry, or for settings in which it is not possible to perform
spirometry. Because those other measurements may be used to generate a
non-invasive, continuous signal that indicates the efficacy of
stimulating the selected nerves, they will be discussed below in
connection with their use to provide a feedback signal in the present
invention, for adjusting the power of the applied impulse, as well as for
adjustment of other stimulation parameters. It should be noted here that
one of them, the interrupter technique (Rint) measures airway resistance,
which according to Poiseuille's Law for laminar air flow, is inversely
proportional to the fourth power of the caliber of dilation of the
bronchi.

[0083]The measurement of FEV1 entails first measuring forced
expiration volume as a function of time (the maximum expiratory
flow-volume curve, or MEFV, which may be depicted in different ways,
e.g., normalized to percentage of vital capacity), then reading the value
of the MEFV curve at the one second point. Because a single parameter
such as FEV1 cannot characterize the entire MEFV curve, it is
understood that the MEFV curve itself (or a set of parameters derived
from it) more accurately represents the patient's respiratory status than
the FEV1 value alone [Francois HAAS, Kenneth Axen, and John Salazar
Schicchi. Use of Maximum Expiratory Flow-Volume Curve Parameters in the
Assessment of Exercise-induced Bronchospasm. Chest 1993; 103:64-68].
Furthermore, it is understood that in order to understand the functional
relationship between the magnitude of bronchoconstriction (literally, a
reduction in the average caliber of bronchial lumen) and FEV1, one
does so by first considering the relation of each of them to the MEFV
curve [Rodney K. LAMBERT and Theodore A. Wilson. Smooth muscle dynamics
and maximal expiratory flow in asthma. J Appl Physiol 99: 1885-1890,
2005].

[0084]As will be discussed below in connection with a detailed description
of our experiments that were only summarized above, applicants have
disclosed a system and method for increasing a patient's FEV1 in a
relatively short period of time. Preferably, the impulse of energy
applied to the patient is sufficient to increase the FEV1 of the
patient by a clinically significant amount in a period of time less than
about 6 hours, preferably less than 3 hours and more preferably less than
90 minutes. In an exemplary embodiment, the clinically significant
increase in FEV1 occurs in less than 15 minutes. A clinically
significant amount is defined herein as at least a 12% increase in the
patient's FEV1 versus the FEV1 prior to application of the
electrical impulse.

[0085]In the preferred embodiment of the present invention, a magnetic
stimulator is used to stimulate selected nerve fibers, particularly the
vagus nerve. Magnetic stimulation has been used by several investigators
to non-invasively stimulate the vagus nerve. As indicated above, such
magnetic stimulation involves the application of a time-varying magnetic
field to induce electric currents and fields within tissue. However, none
of the following reports of magnetic stimulation of the vagus nerve were
related to the treatment of bronchoconstriction. In a series of articles
beginning in 1992, Aziz and colleagues describe using non-invasive
magnetic stimulation to electrically stimulate the vagus nerve in the
neck. [Q. AZIZ et al. Magnetic Stimulation of Efferent Neural Pathways to
the Human Oesophagus. Gut 33: S53-S70 (Poster Session F218) (1992); AZIZ,
Q., J. C. Rothwell, J. Barlow, A. Hobson, S. Alani, J. Bancewicz, and D.
G. Thompson. Esophageal myoelectric responses to magnetic stimulation of
the human cortex and the extracranial vagus nerve. Am. J. Physiol. 267
(Gastrointest. Liver Physiol. 30): G827-G835, 1994; Shaheen HAMDY, Qasim
Aziz, John C. Rothwell, Anthony Hobson, Josephine Barlow, and David G.
Thompson. Cranial nerve modulation of human cortical swallowing motor
pathways. Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35):
G802-G808, 1997; Shaheen HAMDY, John C. Rothwell, Qasim Aziz, Krishna D.
Singh, and David G. Thompson. Long-term reorganization of human motor
cortex driven by short-term sensory stimulation. Nature Neuroscience 1
(issue 1, May 1998):64-68.] SIMS and colleagues stimulated the vagus
nerve at and near the mastoid tip. [H. Steven SIMS, Toshiyuki Yamashita,
Karen Rhew, and Christy L. Ludlow. Assessing the clinical utility of the
magnetic stimulator for measuring response latencies in the laryngeal
muscles. Otolaryngol Head Neck Surg 1996; 114:761-7]. KHEDR and
colleagues also used a magnetic stimulator to stimulate the vagus nerve
at the tip of the mastoid bone [E. M. KHEDR and E-E. M. Aref
Electrophysiological study of vocal-fold mobility disorders using a
magnetic stimulator. European Journal of Neurology 2002, 9: 259-267;
KHEDR, E. M., Abo-Elfetoh, N., Ahmed, M. A., Kamel, N. F., Farook, M., El
Karn, M. F. Dysphagia and hemispheric stroke: A transcranial magnetic
study. Neurophysiologie Clinique/Clinical Neurophysiology (2008) 38,
235-242)]. SHAFIK stimulated the vagus nerve in the neck, placing the
magnetic stimulator on the neck between the sternomastoid muscle and the
trachea. [A. SHAFIK. Functional magnetic stimulation of the vagus nerve
enhances colonic transit time in healthy volunteers. Tech Coloproctol
(1999) 3:123-12]. Among these investigations, the one by SHAFIK
stimulated the vagus nerve for the longest period of time. He stimulated
at 175 joules per pulse, 40 Hz frequency, 10 seconds on, 10 seconds off
for 20 minutes duration and followed by 60 minutes of rest, and this
sequence was performed for 5 cycles in each subject. Also, in U.S. Pat.
No. 7,657,310, entitled Treatment of reproductive endocrine disorders by
vagus nerve stimulation, to William R. Buras, there is mention of
electrical stimulation of the vagus nerve "in combination with a magnetic
signal, such as transcranial magnetic stimulation (TMS)". However, that
patent relates to invasive nerve stimulation and is unrelated to the
treatment of bronchoconstriction, as are all the other above-mentioned
magnetic stimulations of the vagus nerve.

[0087]FIG. 1 is a schematic diagram of a nerve modulating device 300 for
delivering impulses of energy to nerves for the treatment of bronchial
constriction or hypotension associated with anaphylactic shock, COPD or
asthma. As shown, device 300 may include an impulse generator 310; a
power source 320 coupled to the impulse generator 310; a control unit 330
in communication with the impulse generator 310 and coupled to the power
source 320; and a magnetic stimulator coil 340 coupled via wires to
impulse generator coil 310. The control unit 330 may control the impulse
generator 310 for generation of a signal suitable for amelioration of the
bronchial constriction or hypotension when the signal is applied to the
nerve non-invasively via the magnetic stimulator coil 340. It is noted
that nerve modulating device 300 may be referred to by its function as a
pulse generator. U.S. Patent Application Publications 2005/0075701 and
2005/0075702, both to Shafer, both of which are incorporated herein by
reference, relating to stimulation of neurons of the sympathetic nervous
system to attenuate an immune response, contain descriptions of pulse
generators that may be applicable to the present invention, when adapted
for use with a magnetic stimulator coil.

[0088]In the preferred embodiment, the vagus nerve will be stimulated in
the patient's neck, where it is situated within the carotid sheath, near
the carotid artery and the interior jugular vein. The carotid sheath is
located at the lateral boundary of the retopharyngeal space on each side
of the neck and deep to the sternocleidomastoid muscle. The left vagus
nerve is selected for stimulation because stimulation of the right vagus
nerve may produce unwanted effects on the heart.

[0089]The three major structures within the carotid sheath are the common
carotid artery, the internal jugular vein and the vagus nerve. The
carotid artery lies medial to the internal jugular vein, and the vagus
nerve is situated posteriorly between the two vessels. Typically, the
location of the carotid sheath or interior jugular vein in a patient (and
therefore the location of the vagus nerve) will be ascertained in any
manner known in the art, e.g., by feel or ultrasound imaging. Proceeding
from the skin of the neck above the sternocleidomastoid muscle to the
vagus nerve, a line would pass successively through the
sternocleidomastoid muscle, the carotid sheath and the internal jugular
vein, unless the position on the skin is immediately to either side of
the external jugular vein. In the latter case, the line may pass
successively through only the sternocleidomastoid muscle and the carotid
sheath before encountering the vagus nerve, missing the interior jugular
vein. Accordingly, a point on the neck adjacent to the external jugular
vein is the preferred location for non-invasive stimulation of the vagus
nerve. In the preferred embodiment, the magnetic stimulator coil would be
centered on such a point, at the level of about the fifth to sixth
cervical vertebra.

[0090]Signal generators for magnetic stimulators have been described for
commercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETIC
STIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,
Carmarthenshire, SA34 0HR, United Kingdom, 2006], as well as for custom
designs for a control unit 330, impulse generator 310 and power source
320 [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, and Wentai Liu. Magnetic
Stimulation of Neural Tissue Techniques and System Design. pp 293-352,
In: Implantable Neural Prostheses 1, Devices and Applications, D. Zhou
and E. Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.
7,744,523, entitled Drive circuit for magnetic stimulation, to Charles M.
Epstein; U.S. Pat. No. 5,718,662, entitled Apparatus for the magnetic
stimulation of cells or tissue, to Reza Jalinous; U.S. Pat. No.
5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, to
Poison]. Magnetic nerve stimulators use a high current impulse generator
310 that may produce discharge currents of 5,000 amps or more, which is
passed through the stimulator coil 340, and which thereby produces a
magnetic pulse. Typically, a transformer charges a capacitor in the
impulse generator 310, which also contains circuit elements that limit
the effect of undesirable electrical transients. Charging of the
capacitor is under the control of a control unit 330, which accepts
information such as the capacitor voltage, power and other parameters set
by the user, as well as from various safety interlocks within the
equipment that ensure proper operation, and the capacitor is then
discharged through the coil via an electronic switch (e.g., a controlled
rectifier) when the user wishes to apply the stimulus.

[0091]Greater flexibility is obtained by adding to the impulse generator a
bank of capacitors that can be discharged at different times. Thus,
higher impulse rates may be achieved by discharging capacitors in the
bank sequentially, such that recharging of capacitors is performed while
other capacitors in the bank are being discharged. Furthermore, by
discharging some capacitors while the discharge of other capacitors is in
progress, by discharging the capacitors through resistors having variable
resistance, and by controlling the polarity of the discharge, the control
unit may synthesize pulse shapes that approximate an arbitrary function.

[0092]The control unit 330 also comprises a general purpose computer,
comprising one or more CPU, computer memories for the storage of
executable computer programs (including the system's operating system)
and the storage and retrieval of data, disk storage devices,
communication devices (such as serial and USB ports) for accepting
external signals from the system's keyboard and computer mouse as well as
externally supplied physiological signals, analog-to-digital converters
for digitizing externally supplied analog signals, communication devices
for the transmission and receipt of data to and from external devices
such as printers and modems that comprise part of the system, hardware
for generating the display of information on monitors that comprise part
of the system, and busses to interconnect the above-mentioned components.
Thus, the user operates the system primarily by typing instructions for
the control unit 330 at a device such as a keyboard and views the results
on a device such as the system's computer monitor, or directs the results
to a printer, modem, and/or storage disk.

[0093]Parameters of stimulation include power level, frequency and train
duration (or pulse number). The stimulation characteristics of each
magnetic pulse, such as depth of penetration, strength and accuracy,
depend on the rise time, peak electrical energy transferred to the coil
and the spatial distribution of the field. The rise time and peak coil
energy are governed by the electrical characteristics of the magnetic
stimulator and stimulating coil, whereas the spatial distribution of the
induced electric field depends on the coil geometry and the anatomy of
the region of induced current flow. In one embodiment of the invention,
pulse parameters are set in such as way as to account for the detailed
anatomy surrounding the nerve that is being stimulated [Bartosz SAWICKI,
Robert Szmurlo, Przemyslaw Plonecki, Jacek Starzy ski, Stanislaw
Wincenciak, Andrzej Rysz. Mathematical Modelling of Vagus Nerve
Stimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Health and
Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008]. A single
pulse may be monophasic (no current reversal within the coil), biphasic
or polyphasic. For rapid rate stimulators, biphasic systems are used
wherein energy is recovered from each pulse in order to help energize the
next. Embodiments of the invention include those that are fixed
frequency, where each pulse in a train has the same interstimulus
interval, and those that have modulated frequency, where the intervals
between each pulse in a train can be varied.

[0096]Toroidal coils with high permeability cores have been theoretically
shown to greatly reduce the currents required for transcranial (TMS) and
other forms of magnetic stimulation, but only if the toroids are embedded
in a conducting medium and placed against tissue with no air interface.
This is difficult to do in practice because the tissue contours (head for
TMS, arms, legs, neck, etc. for peripheral nerve stimulation) are not
planar. To solve this problem, in the preferred embodiment of the present
invention, the toroidal coil is embedded in a balloon-like structure
which is filled with a conducting medium (e.g., a saline solution) with
the same conductivity as muscle tissue. The container itself is made of a
conducting elastomer. In other embodiments of the invention, the
conducting medium may be a balloon filled with a conducting gel or
conducting powders, or the balloon may be constructed extensively from
deformable conducting elastomers. The balloon conforms to the skin
surface removing any air, thus allowing for high impedance matching and
conduction of large electric fields in to the tissue. A device such as
that disclosed in U.S. Pat. No. 7,591,776, entitled Magnetic stimulators
and stimulating coils, to Phillips et al. may conform the coil itself to
the contours of the body, but in the preferred embodiment, such a curved
coil is also enclosed by a container that is filled with a conducting
medium.

[0097]The container of electrically conducting medium is identified as 350
in FIG. 1. As shown there, the container of electrically conducting
medium 350 not only encloses the magnetic stimulator coil, but in the
preferred embodiment is also deformable such that it is form-fitting when
applied to the surface of the body. Thus, the sinuousness or curvature
shown at the outer surface of the container of electrically conducting
medium 350 correspond also to sinuousness or curvature on the surface of
the body, against which the container 350 is applied so as to make the
container and body surface contiguous. Use of the container of conducting
medium 350 allows one to generate (induce) electric fields in tissue (and
electric field gradients and electric currents) that are equivalent to
those generated using current magnetic stimulation devices, but with 1/10
to 1/1000 of the current applied to the magnetic coil. This allows for
minimal heating and deeper tissue stimulation.

[0098]The design and methods of use of impulse generators, control units,
and stimulator coils for magnetic stimulators are informed by the designs
and methods of use of impulse generators, control units, and electrodes
(with leads) for comparable completely electrical nerve stimulators, but
design and methods of use of the magnetic stimulators must take into
account many special considerations, making it generally not
straightforward to transfer knowledge of completely electrical
stimulation methods to magnetic stimulation methods. Such considerations
include determining the anatomical location of the stimulation and
determining the appropriate pulse configuration [OLNEY R K, So Y T,
Goodin D S, Aminoff M J. A comparison of magnetic and electric
stimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.
NILSSON, M. Panizza, B. J. Roth et al. Determining the site of
stimulation during magnetic stimulation of the peripheral nerve,
Electroencephalographs and clinical neurophysiology. vol 85, pp. 253-264,
1992; Nafia AL-MUTAWALY, Hubert de Bruin, and Gary Hasey. The Effects of
Pulse Configuration on Magnetic Stimulation. Journal of Clinical
Neurophysiology 20(5):361-370, 2003].

[0099]Furthermore, a potential practical disadvantage of using magnetic
stimulator coils is that they may overheat when used over an extended
period of time. Use of the above-mentioned toroidal coil and container of
electrically conducting medium addresses this potential disadvantage.
However, because of the poor coupling between the stimulating coils and
the nerve tissue, large currents are nevertheless required to reach
threshold electric fields. At high repetition rates, these currents can
heat the coils to unacceptable levels in seconds to minutes depending on
the power levels and pulse durations and rates. Two approaches to
overcome heating are to cool the coils with flowing water or air or to
increase the magnetic fields using ferrite cores (thus allowing smaller
currents). For some applications where relatively long treatment times at
high stimulation frequencies may be required, e.g. treating acute asthma
attacks by stimulating the vagus nerve, neither of these two approaches
are adequate. Water-cooled coils overheat in a few minutes. Ferrite core
coils heat more slowly due to the lower currents and heat capacity of the
ferrite core, but also cool off more slowly and do not allow for
water-cooling since the ferrite core takes up the volume where the
cooling water would flow.

[0100]A solution to this problem is to use a fluid which contains
ferromagnetic particles in suspension like a ferrofluid, or
magnetorheological fluid as the cooling material. Ferrofluids are
colloidal mixtures composed of nanoscale ferromagnetic, or ferrimagnetic,
particles suspended in a carrier fluid, usually an organic solvent or
water. The ferromagnetic nanoparticles are coated with a surfactant to
prevent their agglomeration (due to van der Waals forces and magnetic
forces). Ferrofluids have a higher heat capacity than water and will thus
act as better coolants. In addition, the fluid will act as a ferrite core
to increase the magnetic field strength. Also, since ferrofluids are
paramagnetic, they obey Curie's law, and thus become less magnetic at
higher temperatures. The strong magnetic field created by the magnetic
stimulator coil will attract cold ferrofluid more than hot ferrofluid
thus forcing the heated ferrofluid away from the coil. Thus, cooling may
not require pumping of the ferrofluid through the coil, but only a simple
convective system for cooling. This is an efficient cooling method which
may require no additional energy input [U.S. Pat. No. 7,396,326 and
published applications US2008/0114199, US2008/0177128, and
US2008/0224808, all entitled Ferrofluid cooling and acoustical noise
reduction in magnetic stimulators, respectively to Ghiron et al., Riehl
et al., Riehl et al. and Ghiron et al.].

[0101]Magnetorheological fluids are similar to ferrofluids but contain
larger magnetic particles which have multiple magnetic domains rather
than the single domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magneto
sensitive fluid composition and a process for preparation thereof, to
John et al.]. They can have a significantly higher magnetic permeability
than ferrofluids and a higher volume fraction of iron to carrier.
Combinations of magnetorheological and ferrofluids may also be used [M T
LOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D G
Duran. Magnetorheology for suspensions of solid particles dispersed in
ferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; Ladislau
VEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Science and
Technology Vol. 54 (2008) pp 127-136.]. Accordingly, in the preferred
embodiment, overheating is minimized by cooling the magnetic stimulator
coil 340 with a ferrofluid and/or magnetorheological fluid and/or a
mixture or combination of ferrofluid and magnetorheological fluids.

[0102]In the preferred embodiment, overheating of the magnetic stimulator
coil 340 may also be minimized by optionally restricting the magnetic
stimulation to particular phases of the respiratory cycle, allowing the
coil to cool during the other phases of the respiratory cycle.
Alternatively, greater peak power may be achieved per respiratory cycle
by concentrating all the energy of the magnetic pulses into selected
phases of the respiratory cycle. Detection of the phase of respiration
may be performed non-invasively by adhering a thermistor or thermocouple
probe to the patient's cheek so as to position the probe at the nasal
orifice. Strain gauge signals from belts strapped around the chest, as
well as inductive plethysmography and impedance pneumography, are also
used traditionally to non-invasively generate a signal that rises and
falls as a function of the phase of respiration. After digitizing such
signals, the phase of respiration may be determined using open source
software such as the one called "puka", which is part of PhysioToolkit, a
large published library of open source software and user manuals that are
used to process and display a wide range of physiological signals
[GOLDBERGER A L, Amaral L A N, Glass L, Hausdorff J M, Ivanov P Ch, Mark
R G, Mietus J E, Moody G B, Peng C K, Stanley H E. PhysioBank,
PhysioToolkit, and PhysioNet: Components of a New Research Resource for
Complex Physiologic Signals. Circulation 101(23):e215-e220 (2000);
available from PhysioNet, M.I.T. Room E25-505A, 77 Massachusetts Avenue,
Cambridge, Mass. 02139]. In one embodiment of the present invention, the
control unit 330 contains an analog-to-digital converter to receive such
analog respiratory signals, and software for the analysis of the
digitized respiratory waveform resides within the control unit 330. That
software extracts turning points within the respiratory waveform, such as
end-expiration and end-inspiration, and forecasts future turning-points,
based upon the frequency with which waveforms from previous breaths match
a partial waveform for the current breath. The control unit 330 then
controls the impulse generator 310 to stimulate the selected nerve only
during a selected phase of respiration, such as all of inspiration or
only the first second of inspiration, or only the expected middle half of
inspiration.

[0103]In the preferred embodiment, physiological signals in addition to
those related to the determination of respiratory phase are measured
non-invasively. The additional signals comprise the electrocardiogram,
measured by one or more chest electrocardiographic leads; the arterial
blood pressure measured non-invasively and continuously with an arterial
tonometer applied to patient's wrist; and a pulse oximeter applied to the
patient's fingertip. The electrocardiographic electrodes may also be used
to measure transthoracic impedance, so as to obtain a signal that rises
and falls according to the phase of respiration. A respiration signal may
also be obtained from the actual electrocardiographic signal, using
computer programs available in the PhysioToolkit software library that
was mentioned above. In embodiments of the present invention, the control
unit 330 contains analog-to-digital converters to receive such analog
physiological signals, and software for the analysis of the signal
waveforms resides within the control unit 330. In particular, the heart
rate is derived from the electrocardiographic signals using open source
software such as the QRS detectors and heart rate tachometers that are
available in the PhysioToolkit software library, and the systolic,
diastolic, and mean blood pressure are derived from the blood pressure
waveform using software for pulse detection that is also available in the
PhysioToolkit software library.

[0104]In our experiments that were summarized above (and will be described
in detail below), the location and parameters of the electrical impulses
delivered to the vagus nerve were optimized to stimulate the release of
hormones into the circulation, at concentrations that produce bronchial
smooth muscle relaxation, and that also have little effect on heart rate
or blood pressure. For bronchoconstricted patients with normal heart
rates and blood pressure, those are the stimulation location and
parameters of choice. However, during asthma or COPD attacks or
anaphylactic shock, it is sometimes the case that a significant increase
or decrease in heart rate accompanies airway constriction. In cases of
unsafe or suboptimal heart rates, the teachings of the present invention
permit not only prompt airway dilation, but also an improved heart rate,
to enable subsequent life saving measures that otherwise would be
ineffective or impossible due to severe constriction or other
physiological effects. Treatment in accordance with the present invention
provides not only bronchodilation, but also optionally improved heart
function for a long enough period of time that administered medication
such as epinephrine has time to take effect before the patient
suffocates. This is because, depending on the placement of the impulse to
the selected nerve fiber, the stimulating, blocking and/or modulating
signal can also improve the heart function, by potentially elevating or
decreasing heart rate. Furthermore, as an option in the present
invention, parameters of the stimulation may be modulated by the control
unit 330 to control the impulse generator 310 in such a way as to
temporally modulate stimulation by the magnetic stimulator coil 340, in
such a way as to achieve and maintain the heart rate within safe or
desired limits. In that case, the parameters of the stimulation are
individually raised or lowered in increments (power, frequency, etc.),
and the effect as an increased, unchanged, or decreased heart rate is
stored in the memory of the control unit 330. When the heart rate changes
to a value outside the specified range, the control unit 330
automatically resets the parameters to values that had been recorded to
produce a heart rate within that range, or if no heart rate within that
range has yet been achieved, it increases or decreases parameter values
in the direction that previously acquired data indicate would change the
heart rate in the direction towards a heart rate in the desired range.
Similarly, the arterial blood pressure is also recorded non-invasively in
an embodiment of the invention, and as described above, the control unit
330 extracts the systolic, diastolic, and mean arterial blood pressure
from the blood pressure waveform. The control unit 330 will then control
the impulse generator 310 in such a way as to temporally modulate nerve
stimulation by the magnetic stimulator coil 340, in such a way as to
achieve and maintain the blood pressure within predetermined safe or
desired limits, by the same method that was indicated above for the heart
rate. Thus, even if one does not intend to treat bronchoconstriction,
embodiments of the invention described above may be used to achieve and
maintain the heart rate and blood pressure within desired ranges.

[0105]If one does not anticipate problems with overheating the magnetic
stimulator coil 340, it may nevertheless be therapeutically advantageous
to program the control unit 330 to control the impulse generator 310 in
such a way as to temporally modulate stimulation by the magnetic
stimulator coil 340, depending on the phase of the patient's respiration.
In patent application JP2008/081479A, entitled Vagus nerve stimulation
system, to Yoshihoto, a system is also described for keeping the heart
rate within safe limits. When the heart rate is too high, that system
stimulates a patient's vagus nerve, and when the heart rate is too low,
that system tries to achieve stabilization of the heart rate by
stimulating the heart itself, rather than use different parameters to
stimulate the vagus nerve. In that disclosure, vagal stimulation uses an
electrode, which is described as either a surface electrode applied to
the body surface or an electrode introduced to the vicinity of the vagus
nerve via a hypodermic needle. That disclosure is unrelated to the
problem of bronchoconstriction that is addressed herein, but it does
consider stimulation during particular phases of the respiratory cycle,
for the following reason. Because the vagus nerve is near the phrenic
nerve, Yoshihoto indicates that the phrenic nerve will sometimes be
electrically stimulated along with the vagus nerve. The present
applicants did not experience this problem in the experiments reported
below, so the problem may be one of a misplaced electrode. In any case,
the phrenic nerve controls muscular movement of the diaphragm, so
consequently, stimulation of the phrenic nerve causes the patient to
hiccup or experience irregular movement of the diaphragm, or otherwise
experience discomfort. To minimize the effects of irregular diaphragm
movement, Yoshihoto's system is designed to stimulate the phrenic nerve
(and possibly co-stimulate the vagus nerve) only during the inspiration
phase of the respiratory cycle and not during expiration. Furthermore,
the system is designed to gradually increase and then decrease the
magnitude of the electrical stimulation during inspiration (notably
amplitude and stimulus rate) so as to make stimulation of the phrenic
nerve and diaphragm gradual. Patent application publication
US2009/0177252, entitled Synchronization of vagus nerve stimulation with
the cardiac cycle of a patient, to Arthur D. Craig, discloses a method of
treating a medical condition in which the vagus nerve is stimulated
during a portion of the cardiac cycle and the respiratory cycle. That
disclosure pertains to the treatment of a generic medical condition, so
it is not specifically directed to the treatment of bronchoconstriction.
In the present application, stimulation of selected nerve fibers during
particular phases of respiration for the treatment of bronchoconstriction
may be motivated by two physiological considerations. The first is that
contraction of bronchial smooth muscle appears to be intrinsically
rhythmic. It has been reported that bronchial smooth muscle contracts
over two phases, during mid-inspiration and early expiration. When the
vagus efferent nerves are repetitively stimulated with electric pulses,
the bronchus constricted periodically; tonic constriction is almost
absent in the bronchus in response to the vagally mediated descending
commands. [KONDO, Tetsuri, Ichiro Kobayashi, Naoki Hayama, Gen Tazaki,
and Yasuyo Ohta. Respiratory-related bronchial rhythmic constrictions in
the dog with extracorporeal circulation. J Appl Physiol 88: 2031-2036,
2000]. Accordingly, a rationale for stimulating the vagus nerve during
particular phases of the respiratory cycle is that such stimulation may
be used to counteract or inhibit the constriction that occurs naturally
during those specific phases of respiration. If the counteracting or
inhibiting effects occur only after a delay, then the timing of the
stimulation pulses must precede the phases of respiration during which
the contraction would occur, by an interval corresponding to the delay. A
second motivation for stimulating the vagus nerve during particular
phases of respiration is that an increase or decrease in the duration of
subsequent phases of respiration may be produced by applying the
stimulation during particular phases of respiration [M. SAMMON, J. R.
Romaniuk and E. N. Bruce. Bifurcations of the respiratory pattern
produced with phasic vagal stimulation in the rat. J Appl Physiol 75:
912-926, 1993]. In particular, a narrow window may exist at the
expiratory-inspiratory transition in which it may be possible to induce
bursts of inspiratory activity followed by a prolonged breath.
Accordingly, if it is therapeutically beneficial to induce deep breaths,
those breaths might be induced by stimulating during that time-window. In
fact, the physiologically meaningful cycle of stimulation in this case is
not a single respiratory cycle, but is instead a collective sequence of
respiratory cycles, wherein it makes sense only to speak of stimulation
during particular parts of the sequence.

[0106]In some embodiments of the invention, it may also be therapeutically
advantageous to program the control unit 330 to control the impulse
generator 310 in such a way as to modulate stimulation by the magnetic
stimulator coil 340, by modulating the parameters and properties of the
applied impulses, depending on the values of frequently measured
non-invasive indicators of the magnitude of bronchoconstriction. Because
of patient motion, e.g., due to the patient's fidgeting restlessness or
contraction of the sternocleidomastoid muscle, there will inevitably be
some motion of the magnetic stimulator coil 340 relative to the location
of the nerve fibers that are selected for stimulation, no matter how
rigidly the coil 340 and conducting container 350 are comfortably held
against the patient, using a frame and strap similar to those used for
transcranial magnetic stimulation. Therefore, the power of the energy
impulse delivered to the selected nerve fibers would fluctuate or drift
as a function of the fluctuating or drifting distance and angles between
the coil and nerve fiber, unless a method is employed to automatically
adjust the power of the energy impulse for such fluctuations or drift. In
the preferred embodiment, that method makes the adjustment by measuring a
surrogate for FEV1 and then adjusting the power in such a way that
the value of the surrogate measurement does not decrease relative to the
surrogate's previous value averaged over a predetermined number of prior
cycles of respiration. It is understood that the power adjustment may
also occur throughout a single respiratory cycle, particularly when there
is movement due to changing accessory muscle use. Thus, in one embodiment
of the present invention, the control unit 330 contains an
analog-to-digital converter to receive an analog signal that is a
surrogate for FEV1, or it contains a digital interface to receive a
digital signal that is a surrogate for FEV1, and software for the
analysis of the digitized FEV1 surrogate data resides within the
control unit 330. The control unit 330 then sets parameters of the
impulse generation (such as power) to control the impulse generator 310
so as to maintain or move the surrogate FEV1 value to within a
desired range, using the same method that was described above for the
heart rate and blood pressure. It should be noted also that the patient
him/herself may sense an improvement in breathing even before there is a
clear improvement in FEV1 or its surrogates, in which case, verbal
communication between patient and medical provider may be used for
feedback. Accordingly, it is understood that the medical provider may
override the automatic feedback and use the verbal feedback of the
patient to manually adjust stimulation parameters.

[0107]Three types of non-invasive measurements are currently recognized as
being surrogates for the measurement of FEV1: pulsus paradoxus,
accessory muscle use, and airway resistance. In the preferred embodiment,
pulsus paraduxus is measured, which is based on the observation that in
asthmatic patients (as well as other patients experiencing
bronchoconstriction), the patient's blood pressure waveform will rise and
fall as a function of the phase of respiration. In the preferred
embodiment, the blood pressure waveform (and the magnitude of any
accompanying pulsus paradoxus) is measured non-invasively with an
arterial tonometer, that is placed, for example, on the patient's wrist
[James RAYNER, Flor Trespalacios, Jason Machan, Vijaya Potluri, George
Brown, Linda M. Quattrucci, and Gregory D. Jay. Continuous Noninvasive
Measurement of Pulsus Paradoxus Complements Medical Decision Making in
Assessment of Acute Asthma Severity. CHEST 2006; 130:754-765].
Digitization and analysis of the blood pressure waveform may be performed
in a computer dedicated to that purpose, in which case, the numerical
value of the continuously varying pulsus paradoxus signal would be
transferred to the control unit 330 through a digital interface
connecting the control unit 330 and dedicated computer. Alternatively,
the control unit 330 may contain an analog-to-digital converter to
receive the analog tonometric signal, and the analysis of the blood
pressure waveform would be performed within the control unit 330. Instead
of using an arterial tonometer to measure the blood pressure wave form
and any accompanying pulsus paradoxus, it is also possible to use a pulse
oximeter, attached for example, to the patient's finger tip [Donald H
ARNOLD, Cathy A Jenkins, Tina V Hartert. Noninvasive assessment of asthma
severity using pulse oximeter plethysmograph estimate of pulsus paradoxus
physiology. BMC Pulmonary Medicine 2010, 10:17; U.S. Pat. No. 7,044,917
and U.S. Pat. No. 6,869,402, entitled Method and apparatus for measuring
pulsus paradoxus, to Arnold]. A dedicated computer may be used to acquire
and analyze the blood pressure waveform and the magnitude of pulsus
paradoxus, which would be transferred to the control unit 330 as
indicated above for the tonometrically acquired signal, or the analog
pulse oximetry signal may be digitized and processed within the control
unit 330, as indicated above.

[0108]Accessory muscle use may also be used as a surrogate for the
measurement of FEV1 [ARNOLD D H, Gebretsadik T, Minton P A, Higgins
S, Hartert T V: Clinical measures associated with FEV1 in persons with
asthma requiring hospital admission. Am J Emerg Med 2007, 25:425-429].
The accessory muscles are not used during restful, tidal breathing of a
normal patient, but are used during labored breathing. The
sternocleidomastoid muscles are the most important accessory muscles of
inspiration. They run from the mastoid processes to insert along the
medial third of the clavicle. To measure their use, a standard
electromyogram may be performed, the signal from which may be digitized
and transferred to the control unit 330 as indicated above. [T. DE MAYO,
R. Miralles, D. Barrero, A. Bulboa, D. Carvajal, S. Valenzuela, and G.
Ormeno. Breathing type and body position effects on sternocleidomastoid
and suprahyoid EMG activity. Journal of Oral Rehabilitation, Volume 32,
Issue 7, pages 487-494, July 2005; Roberto MERLETTI, Alberto Botter,
Amedeo Troiano, Enrico Merlo, Marco Alessandro Minetto. Technology and
instrumentation for detection and conditioning of the surface
electromyographic signal: State of the art. Clinical Biomechanics 24
(2009) 122-134]. Alternatively, non-invasive plethysmography may be used
to measure accessory muscle use, because as ventilatory demands increase,
these muscles contract to lift the sternum and increase the
anteroposterior diameter of the upper rib cage during inspiration. The
anteroposterior diameter may be measured, for example, by respiratory
inductance plethysmography (RIP) and electrical impedance tomography
(EIT). RIP uses elastic bands around the chest (and abdomen) to assess
changes in lung volume. EIT measures regional impedance changes with
electrodes around the patient's chest, each of them injecting and
receiving small currents. Such impedance changes have been correlated
with dimensional changes of the lung. The plethysmography signal may be
digitized and transferred to the control unit 330 as indicated above, as
a measure of the extent to which rib cage geometry is changing as the
result of accessory muscle use.

[0109]Another surrogate for the measurement of FEV1 is the
measurement of airway resistance [P. D. BRIDGE, H. Lee, M. Silverman. A
portable device based on the interrupter technique to measure
bronchodilator response in schoolchildren. Eur Respir J, 1996, 9,
1368-1373]. Airway resistance is defined as the ratio of the difference
between mean alveolar pressure and airway opening pressure to flow
measured at the mouth, and it may be measured using devices that are
commercially available [e.g., MicroRint, Catalog No. MR5000 from
Micromedical Ltd. and Cardinal Health UK 232 Ltd, The Crescent, Jays
Close, Basingstoke, RG22 4BS, U.K.]. Such devices have a serial or USB
port that permits the control unit 330 to instruct the device to perform
the airway resistance measurement and receive the airway resistance data
in return, via a serial or USB port in the control unit 330. Because the
measurement is necessarily intermittent rather than continuous, and
because it requires the patient to breathe passively through a mouthpiece
or face mask, this surrogate for the measurement of FEV1 is not the
preferred one.

[0110]FIG. 2 illustrates an exemplary electrical voltage/current profile
for a stimulating, blocking and/or modulating impulse applied to a
portion or portions of selected nerves in accordance with an embodiment
of the present invention. For the preferred embodiment, the voltage and
current refer to those that are non-invasively induced within the patient
by the magnetic stimulator. As shown, a suitable electrical
voltage/current profile 400 for the blocking and/or modulating impulse
410 to the portion or portions of a nerve may be achieved using pulse
generator 310. In a preferred embodiment, the pulse generator 310 may be
implemented using a power source 320 and a control unit 330 having, for
instance, a processor, a clock, a memory, etc., to produce a pulse train
420 to the electrode(s) 340 that deliver the stimulating, blocking and/or
modulating impulse 410 to the nerve. Nerve modulating device 300 may be
externally powered and/or recharged may have its own power source 320. By
way of example, device 300 may be purchased commercially.

[0112]In addition, or as an alternative to the devices to implement the
modulation unit for producing the electrical voltage/current profile of
the stimulating, blocking and/or modulating impulse to the magnetic
stimulator coil, the device disclosed in U.S. Patent Publication No.
2005/0216062 (the entire disclosure of which is incorporated herein by
reference), may be employed. U.S. Patent Publication No. 2005/0216062
discloses a multifunctional electrical stimulation (ES) system adapted to
yield output signals for effecting electromagnetic or other forms of
electrical stimulation for a broad spectrum of different biological and
biomedical applications, including magnetic stimulators, which produce a
high intensity magnetic field pulse in order to non-invasively stimulate
nerves. The system includes an ES signal stage having a selector coupled
to a plurality of different signal generators, each producing a signal
having a distinct shape such as a sine, a square or a saw-tooth wave, or
simple or complex pulse, the parameters of which are adjustable in regard
to amplitude, duration, repetition rate and other variables. Examples of
the signals that may be generated by such a system are described in a
publication by Liboff [A. R. LIBOFF. Signal shapes in electromagnetic
therapies: a primer. pp. 17-37 in: Bioelectromagnetic Medicine (Paul J.
Rosch and Marko S. Markov, eds.). New York: Marcel Dekker (2004)]. The
signal from the selected generator in the ES stage is fed to at least one
output stage where it is processed to produce a high or low voltage or
current output of a desired polarity whereby the output stage is capable
of yielding an electrical stimulation signal appropriate for its intended
application. Also included in the system is a measuring stage which
measures and displays the electrical stimulation signal operating on the
substance being treated as well as the outputs of various sensors which
sense conditions prevailing in this substance whereby the user of the
system can manually adjust it or have it automatically adjusted by
feedback to provide an electrical stimulation signal of whatever type he
wishes and the user can then observe the effect of this signal on a
substance being treated. As described above, one aspect of the present
invention is that such feedback is provided by non-invasive sensors
producing signals that may act as surrogates for the measurement of
FEV1.

[0113]The use of feedback to generate the modulation signal 400 may result
in a signal that is not periodic, particularly if the feedback is
produced from sensors that measure naturally occurring, time-varying
aperiodic physiological signals from the patient. In fact, the absence of
significant fluctuation in naturally occurring physiological signals from
a patient is ordinarily considered to be an indication that the patient
is in ill health. This is because a pathological control system that
regulates the patient's physiological variables may have become trapped
around only one of two or more possible steady states and is therefore
unable to respond normally to external and internal stresses.
Accordingly, even if feedback is not used to generate the modulation
signal 400, it may be useful to artificially modulate the signal in an
aperiodic fashion, in such a way as to simulate fluctuations that would
occur naturally in a healthy individual. Thus, the noisy modulation of
the stimulation signal may cause a pathological physiological control
system to be reset or undergo a non-linear phase transition, through a
mechanism known as stochastic resonance. In normal respiratory
physiology, sighing at irregular intervals is thought to bring about such
a resetting of the respiratory control system. Experimentally, noisy
artificial ventilation may increase respiration [B. SUKI, A. Alencar, M.
K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade, E. P. Ingenito,
S. Zapperi, H. E. Stanley, Life-support system benefits from noise,
Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham, Linda G Girling
and John F Brewster. Fractal ventilation enhances respiratory sinus
arrhythmia. Respiratory Research 2005, 6:41]. So, in one embodiment of
the present invention, the modulation signal 400, with or without
feedback, will stimulate the selected nerve fibers in such a way that one
or more of the stimulation parameters (power, frequency, and others
mentioned herein) are varied by sampling a statistical distribution
having a mean corresponding to a selected, or to a most recent
running-averaged value of the parameter, and then setting the value of
the parameter to the randomly sampled value. The sampled statistical
distributions will comprise Gaussian and 1/f, obtained from recorded
naturally occurring random time series or by calculated formula.
Parameter values will be so changed periodically, or at time intervals
that are themselves selected randomly by sampling another statistical
distribution, having a selected mean and coefficient of variation, where
the sampled distributions comprise Gaussian and exponential, obtained
from recorded naturally occurring random time series or by calculated
formula.

[0114]The stimulation device 300, magnetic stimulation coil 340, and
electrically conducting container 350 are preferably selected and
configured to induce a peak pulse voltage in the range from about 0.2
volts to about 20 volts, at or between points in close proximity to the
nerve fibers that are being stimulated.

[0115]The stimulating, blocking and/or modulating impulse signal 410
preferably has a frequency, an amplitude, a duty cycle, a pulse width, a
pulse shape, etc. selected to influence the therapeutic result, namely
stimulating, blocking and/or modulating some or all of the transmission
of the selected nerve. For example the frequency may be about 1 Hz or
greater, such as between about 15 Hz to 50 Hz, more preferably around 25
Hz. The modulation signal may have a pulse width selected to influence
the therapeutic result, such as about 20 microseconds or greater, such as
about 20 microseconds to about 1000 microseconds. The modulation signal
may have a peak voltage amplitude selected to influence the therapeutic
result, such as about 0.2 volts or greater, such as about 0.2 volts to
about 20 volts.

[0116]In a preferred embodiment of the invention, a method of treating
bronchial constriction comprises applying one or more electrical
impulse(s) of a frequency of about 15 Hz to 50 Hz to a selected region of
the vagus nerve to reduce a magnitude of constriction of bronchial smooth
muscle. As discussed in more detail below, applicant has made the
unexpected discovered that applying an electrical impulse to a selected
region of the vagus nerve within this particular frequency range results
in almost immediate and significant improvement in bronchodilation, as
discussed in further detail below. Applicant has further discovered that
applying electrical impulses outside of the selected frequency range (15
Hz to 50 Hz) does not result in immediate and significant improvement in
bronchodilation. Preferably, the frequency is about 25 Hz. In this
embodiment, the induced electrical impulse(s) are of an amplitude of
between about 0.75 to 12 volts and have a pulsed on-time of between about
50 to 500 microseconds, preferably about 200-400 microseconds.

[0117]In accordance with another embodiment, devices in accordance with
the present invention are provided in a "pacemaker" type form, in which
electrical impulses 410 are generated to a selected region of the nerve
by device 300 on an intermittent basis to create in the patient a lower
reactivity of the nerve to upregulation signals.

[0118]In an alternate embodiment, a mechanical vibrator transmits energy
to a nerve, rather than a magnetic stimulator. In 1932, Hill demonstrated
that the human vagus nerve in the neck may be excited in some individuals
by purely mechanical means [Ian G. W. HILL. Stimulation of the vagus
nerve and carotid sinus in man. Experimental Physiology (1932) 22,
79-93]. That demonstration took place during invasive surgical
interventions, and the mechanical stimulation involved only manual
percussion pressure. His investigations were motivated by the fact that
the vagus nerve may be stimulated by carotid massage on the neck near the
carotid body (as well as by Valsalva maneuver, ocular pressure, digital
rectal massage, and head-up tilting), which is performed in order to
investigate causes of syncope or to treat supraventricular tachycardia.
Cardioinhibitory responses may result from the massage (decreased heart
rate and heart contractility, due to enhanced parasympathetic tone), as
well as a drop in blood pressure (due to vasodilation of blood vessels in
the legs, probably due to a decrease in sympathetic nervous system tone).
Although carotid massage is known to dilate blood vessels in the legs, it
is not known to do so in the bronchi and is therefore not used to produce
bronchodiation. Subsequent investigators demonstrated that the vagus
nerve may be stimulated mechanically at a location where it leaves the
brainstem [Vladimir SHUSTERMAN, Peter J. Jannetta, Benhur Aysin, Anna
Beigel, Maksim Glukhovskoy, and Irmute Usiene. Direct Mechanical
Stimulation of Brainstem Modulates Cardiac Rhythm and Repolarization in
Humans. Journal of Electrocardiology Vol. 35 Supplement 2002, pp.
247-256]. That mechanical stimulation also took place during invasive
surgery, and the stimulation occurred at 1 to 2 Hertz with a duration of
1 minute. Afferent nerves carried by the auricular branch of the vagus
nerve (also known as Arnold nerve and Alderman's nerve) also innervate
the external auditory meatus. When mechanically stimulated, in some
individuals they may elicit the Arnold's ear-cough reflex that is similar
to a reflex that may be elicited by stimulating other branches of the
vagus nerve. [TEKDEMIR I, Aslan A, Elhan A. A clinico-anatomic study of
the auricular branch of the vagus nerve and Arnold's ear-cough reflex.
Surg Radiol Anat 1998; 20:253-257].

[0119]Non-invasive mechanical stimulation of the vagus nerve at the ear is
disclosed in patent application US2008/0249439, entitled Treatment of
Inflammation by Non-Invasive Stimulation, to Tracey et al., which is
directed to stimulating a subject's inflammatory reflex in a manner that
significantly reduces proinflammatory cytokines in the subject. To
achieve that effect, Tracey et al. disclosed that an effective mechanical
stimulation frequency is between about 50 and 500 Hz. They claim their
method for treatment of a long list of diseases, including allergy,
anaphylactic shock, bronchitis, emphysema, and adult respiratory distress
syndrome. However, they make no mention of bronchial constriction or
bronchodilation. They also say that the effect that their method has on
smooth muscle cells (among many other cell types in a list) is to
modulate their production of proinflammatory cytokines, but their
application makes no mention of their method modulating the contractile
properties of smooth muscle cells. Thus, if the non-invasive method that
they disclose is useful for the treatment of asthma, anaphylactic shock,
or chronic obstructive pulmonary disease, there is no motivation or
suggestion that such usefulness would be related to relaxation of the
bronchial smooth muscle. In fact, in a review article concerning the
inflammatory reflex [Kevin J. TRACEY. The inflammatory reflex. NATURE
Vol. 420 (19/26 Dec. 2002) 853-859], the author of the review article and
co-applicant for patent application US2008/0249439, Kevin J. Tracey,
makes no mention of bronchoconstriction, and he only refers to smooth
muscle implicitly in reference to the smooth muscle of arterioles, when
he states that stimulation of the vagus nerve to dilate arterioles is
distinct from stimulation of the vagus nerve to inhibit the inflammatory
reflex. Thus, in that review, Tracey writes (p. 585): "Stimulation of
efferent vagus nerve activity has been associated classically with
slowing heart rate, induction of gastric motility, dilation of arterioles
and constriction of pupils. Inhibition of the inflammatory response can
now be added to this list."

[0120]U.S. Pat. No. 4,966,164, entitled Combined sound generating device
and electrical acupuncture device and method for using the same, to
Colsen et al., discloses sound/electroacupuncture that also stimulates
the ear mechanically, using a buzzer operating in the range of 0.5 to 20
Hz. However, the buzzer is provided in order to provide auditory
stimulation, rather than the stimulation of acupuncture meridian points.
Furthermore, the disclosure by Colsen et al. does not mention use of
their invention to treat bronchoconstriction. Of note is the fact that
U.S. Pat. No. 4,966,164 discloses stimulation in the ear with mechanical
frequencies in the range 0.5 to 20 Hz, and the aforementioned application
US2008/0249439 discloses stimulation in the ear with mechanical
frequencies in range of between 50 and 500 Hz, but neither discloses the
use of mechanical vibrations in the intervening range of greater than 20
Hz and less than 50 Hz.

[0121]FIG. 3 illustrates an alternate embodiment of the invention, in
which a mechanical vibrator transmits energy to a nerve. The figure
contains a schematic diagram of a nerve modulating device 500 for
delivering impulses of mechanical energy to nerves for the treatment of
bronchial constriction or hypotension associated with anaphylactic shock,
COPD or asthma. As shown, device 500 may include an impulse generator
510; a power source 520 coupled to the impulse generator 510; a control
unit 530 in communication with the impulse generator 510 and coupled to
the power source 520; and a linear actuator 540 coupled via wires to the
impulse generator coil 510. The control unit 530 may control the impulse
generator 510 for generation of a signal suitable for amelioration of the
bronchial constriction or hypotension, when mechanical vibrations are
applied to the nerve non-invasively using a linear actuator 540.

[0122]It is noted that nerve modulating device 500 may be referred to by
its function as a pulse generator. U.S. Patent Application Publications
2005/0075701 and 2005/0075702, both to Shafer, both of which are
incorporated herein by reference, relating to stimulation of neurons of
the sympathetic nervous system to attenuate an immune response, contain
descriptions of pulse generators that may be applicable to the present
invention, when adapted to drive a mechanical vibrator.

[0123]In the preferred embodiment, mechanical vibrations are produced by a
linear actuator 540 as shown in FIG. 3 [BOLDEA, I. and Nasar, S. A.
Linear electric actuators and generators. IEEE Transactions on Energy
Conversion. Vol. 14 Issue: 3 (September 1999): 712-717; Bill BLACK, Mike
Lopez, and Anthony Marcos. Basics of voice coil actuators. Power
Conversion and Intelligent Motion (PCIM) July 1993: 44-46]. In alternate
embodiments, vibrations that are applied to the nerve may be produced by
any device that is known in the art to be capable of generating
appropriate mechanical vibration, including (but not limited to): an
electromagnet, a bimorph, a piezo crystal, an electrostatic actuator, a
speaker coil, and a rotating magnet or mass. Ultrasound may also be used
to produce vibrations at frequencies lower than ultrasonic frequencies
[U.S. Pat. No. 5,903,516, entitled Acoustic force generator for
detection, imaging and information transmission using the beat signal of
multiple intersecting sonic beams, to Greenleaf et al.; U.S. Pat. No.
7,753,847, entitled Ultrasound vibrometry, to Greenleaf et al.; U.S. Pat.
No. 7,699,768, entitled Device and method for non-invasive, localized
neural stimulation utilizing hall effect phenomenon, to Kishawi]. In some
embodiments, mechanical vibration is delivered non-invasively using
devices like those that are applied to the skin to reduce pain (vibratory
analgesia) [Elizabeth A. ROY, Mark Hollins, William Maixner. Reduction of
TMD pain by high-frequency vibration: a spatial and temporal analysis.
Pain 101 (2003) 267-274; Kevin C SMITH, Stephen L Comite, Suprina
Balasubramanian, Alan Carver and Judy F Liu. Vibration anesthesia: A
noninvasive method of reducing discomfort prior to dermatologic
procedures. Dermatology Online Journal 10 (2): 1 (2004).]. Multiple
sources of vibration may also be used and applied at one or more
locations on the surface of the body.

[0124]The linear actuator 540 shown in FIG. 3 comprises two separable
parts: a coil holder that is PI (Π)-shaped in cross-section (544), and
a magnet-holder that is E-shaped in cross-section (548). The coil holder
544 is a cylinder (shown in FIG. 3 as legs of the Π in cross section)
that is open on one end and typically closed on the other end. The closed
part is shown in FIG. 3 as the middle member connecting the legs of the
Π in cross section. A coil of wire 542 is wrapped around or embedded
within the cylindrical part of the coil holder. The coil 542 is shown in
cross section in FIG. 3 as a series of blackened circles along both legs
of the Π. A pair of lead wires emerge from the coil 542 and then from
the coil holder 544. They are attached to the impulse generator 510, such
that electrical current may pass into one of the lead wires, through the
coil, and out the other lead wire.

[0125]Air-gaps separate the coil holder 544 from magnet-holder 548, so
that the two parts may slide relative to one another. The outside part of
the magnet holder 584 is cylindrical (shown in cross section in FIG. 3 as
the top and bottom horizontal lines of an E), and permanent magnets 546
are embedded on the inside diameter of that outer cylinder, such that the
magnets facing the coil 542 across an air gap are all of the same
polarity. In the preferred embodiment, the magnets are made of rare-earth
materials. The outer cylinder is ferromagnetic, and an inner core of
ferromagnetic material is attached to it (shown in cross section in FIG.
3 as the middle horizontal line of an E, attached to the outer cylinder
of the magnet holder by the vertical line of an E). The magnetic field
generated by the permanent magnets 546 is oriented radially, and the
ferromagnetic components of the magnet holder complete the magnetic
circuit. A Lorentz force is generated axially on the coil (and coil
holder), whenever current is passed through the coil, which will be
proportional to the current multiplied by the magnetic flux density
produced by the magnets. Therefore, when the impulse generator 510
produces pulses of current in the coil that alternate in sign, the coil
holder will move alternately in opposite directions along its axis, i.e.,
vibrate. The frequency and amplitude of that mechanical vibration are
therefore determined by the frequency and amplitude of current pulses
that are generated by the impulse generator 510.

[0126]An actuator-tip 545 is attached to the closed part of the coil
holder 544. The linear actuator is placed into physical contact with the
surface of the patient's body on the outer surface of the actuator-tip,
which is opposite to the surface of the actuator-tip that is connected to
the coil holder. A stationary surround is used to limit the spread of
vibration across the skin, as follows: a stationary ring is attached, by
an adjustable metal arm, to a table that is mechanically isolated from
the vibratory stimulator. The heavy ring (deformable metal, covered by a
thermal insulator) is positioned onto the patient around the area on the
surface of the skin that is vibrated by the actuator tip, thereby
limiting vibration across the skin. The shape of the actuator-tip surface
that contacts the patient need not be circular, and need not even lie in
a plane, but may instead be selected to have some other shape such as
rectangular or hemispherical or even threaded for attachment to another
piece. The actuator-tip is preferably detachable so as to accommodate
different tip shapes for different applications. In the preferred
embodiment of the invention, the actuator tip will be rectangular with a
dimension of approximately 5 mm by 40 mm, with rounded edges so as to
press comfortably against a patient's neck above the vagus nerve, as now
described. Consider the plane of the skin on the neck to define an X-Y
axis, where the X axis is vertical and the Y axis is horizontal for a
standing patient. A Z axis is perpendicular to the X-Y axis, so that if
the actuator tip is straight, and the actuator is positioned parallel to
the Z axis (perpendicular to the skin of the neck), vibrations will push
the skin in the Z axis, perpendicular to the plane of the skin of the
neck. In another embodiment, the actuator tip is L shaped, and the
actuator is positioned parallel to the X-Y axis. When the actuator tip is
then pressed against the skin, it will vibrate the skin within the X-Y
plane. As the actuator is rotated about the point of skin-tip contact, it
will vibrate the skin in the direction of the X axis, the Y axis, and
intermediate angles within the X-Y plane. In the preferred embodiment,
vibration is in the Z axis, perpendicular to the skin of the neck.

[0127]Proceeding from the skin of the neck above the sternocleidomastoid
muscle to the vagus nerve, a line would pass successively through the
sternocleidomastoid muscle, the carotid sheath and the internal jugular
vein, unless the position on the skin is immediately to either side of
the external jugular vein. In the latter case, the line may pass
successively through only the sternocleidomastoid muscle and the carotid
sheath before encountering the vagus nerve, missing the interior jugular
vein. Accordingly, a point on the neck adjacent to the external jugular
vein is the preferred location for non-invasive stimulation of the vagus
nerve. In the preferred embodiment, the mechanical vibrator would be
centered on such a point, at the level of about the fifth to sixth
cervical vertebra. For a rectangular actuator-tip, the long sides of the
rectangle will be placed parallel to the route of the vagus nerve in the
neck. Typically, the location of the carotid sheath or jugular veins in a
patient (and therefore the location of the vagus nerve) will be
ascertained in any manner known in the art, e.g., by feel or ultrasound
imaging.

[0128]Considering that the nerve stimulating device 300 in FIG. 1 and the
nerve stimulating device 500 in FIG. 3 both control electrical currents
within a coil of wire, their functions are analogous, except that one
stimulates nerves via the pulse of a magnetic field, and the other
stimulates nerves via a pulse of vibration. Accordingly, the features
recited for the nerve stimulating device 300, such as its use for
feedback involving FEV1 surrogates, control of the heart rate and
blood pressure, stimulation during selected phases of the respiratory
cycle, and preferred frequency of stimulation, apply as well to the nerve
stimulating device 500 and will not be repeated here. The preferred
parameters for each nerve stimulating device are those that produce the
effects described below in connection with the detailed description our
experiments.

[0129]In another embodiment of the invention, a selected nerve is
stimulated by delivering to it impulses of light and/or heat energy.
Because absorption and scattering of light increases exponentially with
depth, little irradiated light at wavelengths below 800 nm can traverse
pale human skin, which has a thickness that varies from 1 to 3 mm
depending upon location. At wavelengths above 1,400 nm, there is also
almost no light transmission because of water absorption. Therefore,
infrared wavelengths are ordinarily preferred to irradiate the skin
surface, which can penetrate up to about 4 to 5 millimeters. To stimulate
a nerve non-invasively with light, the nerve must therefore lie very near
the surface of the skin (e.g., vagus nerve at the ear), and infrared
light is preferred. Otherwise, the nerve would have to be irradiated
invasively, using a fiber optic probe.

[0130]The ear canal (external auditory meatus, external acoustic meatus),
is a tube running from the outer ear to the middle ear. The human ear
canal extends from the pinna (auricula, external portion of the ear) to
the eardrum and is about 26 mm in length and 7 mm in diameter. Afferent
nerves carried by the auricular branch of the vagus nerve (ABVN, also
known as Arnold's nerve and Alderman's nerve) innervate the external
auditory meatus. Mechanical stimulation of the ABVN in some individuals
may elicit the Arnold's ear-cough reflex that is similar to a reflex that
may be elicited by stimulating other branches of the vagus nerve.
[TEKDEMIR I, Aslan A, Elhan A. A clinico-anatomic study of the auricular
branch of the vagus nerve and Arnold's ear-cough reflex. Surg Radiol Anat
1998; 20:253-257]. The ABVN exits the skull base via the tympanomastoid
fissure (auricular fissure), approximately 4 mm superior to the
stylomastoid foramen. It divides into two branches outside the cranium,
with one branch running anteriorly to the facial nerve and extending in
the posterior wall of the external acoustic meatus. In dissections of
human cadavers, TEKDEMIR et al. found it to be distributed either
superiorly (in 5 cadavers) or inferiorly (in 3 cadavers) in the external
acoustic meatus. Considering such anatomical variability in the location
of the ABVN that exists between individuals, a device for stimulating the
ABVN should be positionable with two degrees of freedom--a variable
distance of insertion within the external auditory meatus, and a variable
angle of rotation about the line of insertion.

[0131]Stimulation of nerves by light can be separated primarily into three
mechanistic categories: photochemical, photothermal, and photomechanical.
Photochemical effects ordinarily require that a dye be injected into
tissue before applying the light. Photothermal effects rely on the
transformation of absorbed light into heat. Photomechanical effects rely
on laser-induced pressure waves disrupting tissues. After considering
these potential mechanisms, Wells et al. concluded that direct neural
stimulation with laser light is due to photothermal effects, at least
when using infrared light sources. [Jonathon WELLS, Chris Kao, Peter
Konrad, Tom Milner, Jihoon Kim, Anita Mahadevan-Jansen, and E. Duco
Jansen. Biophysical Mechanisms of Transient Optical Stimulation of
Peripheral Nerve. Biophysical Journal Volume 93 Oct. 2007 2567-2580.]
Accordingly, is useful to consider the stimulation of nerves by heat
(thermal pulses) in conjunction with the stimulation of nerves by light.

[0132]In U.S. Pat. No. 7,657,310, entitled Treatment of reproductive
endocrine disorders by vagus nerve stimulation, to William R. Buras,
there is mention of the stimulation of the vagus nerve "by light such as
a laser." However, that patent is concerned with invasive nerve
stimulation and is unrelated to the treatment of bronchoconstriction. As
indicated above, non-invasive stimulation of the vagus nerve using light
(or heat) might be attempted at the ear. However, stimulation at the ear
with light has apparently been attempted only using laser acupuncture
[Peter WHITTAKER. Laser acupuncture: past, present, and future. Lasers in
Medical Science (2004) 19: 69-80], which stimulates acupuncture meridian
points, not nerves. Furthermore, those meridian points are located on the
front and back of the outer ear flap (pinna), not within the external
auditory meatus. Those laser acupuncture applications were successful
when directed to the treatment of pain, smoking cessation, and weight
loss, but as indicated above, acupuncture (including laser acupuncture)
is not considered to be effective for the treatment of asthma or other
disorders associated with bronchoconstriction.

[0133]FIG. 4 is a schematic diagram of a nerve modulating device 800 for
delivering impulses of light and/or heat energy to nerves for the
treatment of bronchial constriction or hypotension associated with
anaphylactic shock, COPD or asthma. As shown, device 800 may include an
impulse generator 810; a power source 820 coupled to the impulse
generator 810; and a control unit 830 in communication with the impulse
generator 810 and coupled to the power source 820. The impulse generator
810 is connected to a light modulator 850 that attenuates the maximum
intensity of a beam of light that is produced by a light source, such
that the intensity of light exiting the light modulator 850 tracks the
magnitude of the electrical signals that are produced by the impulse
generator 810. The light emerging from the light modulator 850 is
directed non-invasively to a selected surface of the external auditory
meatus of a patient, via an optical fiber 854 that is inserted into the
light-emitting earplug 860 at its entrance port 862. The earplug 860 may
be rotated about the optical fiber 854 at the entrance port 862, so that
light reflected by a mirror 864 may pass through a window 866 at a
variable angle of rotation about the line of earplug insertion. The
earplug 860 has an outer diameter that is selected to fit snugly within
the patient's ear canal and is constructed from a material selected for
its flexibility, biocompatability, and ease of insertion and rotation,
such as polytetrafluoroethylene. However, the terminal end of the earplug
868 may be constructed from soft rubber to protect the eardrum from
inadvertent over-insertion of the earplug.

[0134]The light source may be any appropriate source of light having
wavelengths in the range 10-8 meters to 10-3 meters, inclusive, including
(but not limited to): a laser, an incandescent bulb, an arc lamp, a
fluorescent lamp, a light-emitting diode (LED), a super-luminescent diode
(SLD), a laser diode (LD), a cathodoluminescent phosphor that is excited
by an electron beam, a light source such as a fluorescent dye that is
excited by another light source, or a mixture of such light sources
(e.g., cluster probe). In the preferred embodiment, shown in FIG. 4, the
light source is a laser 840. In particular, the preferred light source is
a laser that emits light in the infrared region of the electromagnetic
spectrum, such as a gallium aluminum arsenide laser (wavelength 830 nm)
or a gallium arsenide laser (wavelength 904 nm).

[0135]The light modulator 850 may be any appropriate device for temporally
attenuating the intensity of light that impinges on the light modulator,
including (but not limited to): a movable variable neutral density
filter, a mechanical light chopper wheel, a deformable membrane-mirror,
an acousto-optic light modulator (Bragg cell), an electro-optic light
modulator such as a Pockels cell, a ferroelectric liquid crystal light
modulator, a magneto-optic light modulator, a multiple quantum well light
modulator, rotating crossed polarizers, and a vibrating mirror,
diffraction grating, or hologram. It is also understood that the light
source itself may be rapidly switched on and off or modulated in its
supplied power, in which case the light source and light modulator
840/850 would be combined into a single light modulator and light-source
device. The light modulator may attenuate all rays of the impinging light
by the same amount, or the light modulator may selectively attenuate some
rays of the impinging light so as to shape the beam, as well as to
temporally modulate the intensity of the impinging light.

[0136]For the low-frequency applications described herein (less than
approximately 500 Hz), the light modulator 850 may consist of an
internally blackened (light-absorbing) box with a light-entrance port, to
which one end of optical fiber 844 is attached; a light-exit port, to
which one end of another optical fiber 854 is attached; and within the
box, a positionable, linear variable neutral density filter (e.g.,
Reynard Corp., 1020 Calle Sombra, San Clemente, Calif., USA 92673, Model
R0221Q-10, with useable wavelength range from 200 nm to 2600 nm) having a
position (i.e., neutral density) that is controlled by the impulse
generator 810. For example, the linear variable neutral density filter
may be attached to the tip of a linear actuator like the one shown in
FIG. 3, except that in the present application, the actuator is attached
to the edge of the variable neutral density filter, rather than being
applied to a patient. It is understood that if the light beam has a width
that would cover multiple densities of the variable neutral density
filter, then the light beam may first be focused with a lens onto a
single point of the filter, then collected behind the filter using
another lens.

[0137]In this embodiment, light passes from the laser 840 through the
optical fiber 844 and then enters the modulator box 850 at its entrance
port. When the filter is moved to its open position by the actuator, the
light is essentially unattenuated by the filter, so that a fixed lens can
focus a maximum intensity of light onto the end of optical fiber 854 at
the light-exit port of the light modulator. When the filter is moved to a
closed position by the actuator, light emerging from the optical fiber
844 at the entrance port is attenuated in such a way that essentially no
light enters the optical fiber 854. As the actuator moves the variable
neutral density filter continuously from the open position to the closed
position, the intensity of light entering the optical fiber 854 varies
from a maximum to a minimum, depending on the position of the variable
neutral density filter, which is controlled by the actuator, which is in
turn controlled by the impulse generator 810, which is in turn controlled
by the control unit 830. Thus, by controlling the position of the filter
within the light modulator, the control unit 830 may control the
intensity of the light that enters the optical fiber 854, thereby
controlling the intensity of light entering the light-emitting earplug
860 at its entrance port 862. It is understood in the art that instead of
using a linear actuator, one could use a rotary motor in conjunction with
a mirror or a circular variable neutral density filter that is mounted on
the rotary motor shaft, wherein the angle of the motor shaft is
controlled by an impulse generator; or one could use other light
modulating methods that were mentioned above. It is also understood that
when the light entering the earplug is blocked by the light modulator
850, infrared light may be collected from the surface of the external
auditory meatus by the mirror 864 and optical fiber 862. In one
embodiment of the invention, a beam-splitter is interposed between the
optical fiber 862 and light modulator 850 so that light (black-body
radiation) passing backwards from the ear and through the optical fiber
862 is reflected into an infrared-sensing thermometer [U.S. Pat. No.
6,272,375, entitled Mid infrared transmitting fiber optic based otoscope
for non contact tympanic membrane thermometry, to Katzir et al.; U.S.
Pat. No. 5,167,235, entitled Fiber optic ear thermometer, to Seacord et
al.; U.S. Pat. No. 5,381,796, entitled Ear thermometer radiation
detector, to Francesco Pompei; U.S. Pat. No. 5,790,586, entitled Method
and apparatus for simultaneously illuminating, viewing and measuring the
temperature of a body, to Hilton, Jr. et al.]. When such a thermometer is
present, over-irradiation of the external auditory meatus may be
prevented by sending an auditory meatus-temperature signal to the control
unit 830. In that case, the control unit 830 would attenuate the light by
controlling the light modulator 850 so as to keep the temperature within
a specified safe range. The control unit 830 may also allow light to pass
only during selected phases of the respiratory cycle, so that during
other phases of respiration, excess heat may be transported from the area
of light stimulation by blood vessels of the ear. In another embodiment,
a tube is inserted into the earplug along its side-wall to inject air
that cools the external auditory meatus at the window 866, with another
tube inserted into the earplug near the entrance port 862 to carry or
suck return air from earplug chamber. The air can be injected so as to
maintain constant air pressure within the earplug; or the air pressure
can also pulsate, so as to provide mechanical stimulation to the external
auditory meatus at the window 855, becoming another embodiment of the
mechanical nerve stimulation that was disclosed above.

[0138]The control unit 830 may control the impulse generator 810 for
generation of a signal suitable for amelioration of the bronchial
constriction or hypotension when the signal is applied to the nerve
non-invasively via the light-emitting earplug 860. It is noted that nerve
modulating device 800 may be referred to by its function as a pulse
generator. U.S. Patent Application

[0139]Publications 2005/0075701 and 2005/0075702, both to Shafer, both of
which are incorporated herein by reference, relating to stimulation of
neurons of the sympathetic nervous system to attenuate an immune
response, contain descriptions of pulse generators that may be applicable
to the present invention, when adapted for use with an optical modulator.

[0140]Considering that the nerve stimulating device 300 in FIG. 1 controls
electrical currents within a coil of wire, and as described in the
embodiment above concerning use of a linear actuator to control movement
of a variable light filter, the nerve stimulating device 800 in FIG. 4
also controls electrical currents within a coil of wire in the actuator,
their functions are analogous, except that one stimulates nerves via the
pulse of a magnetic field, and the other stimulates nerves via a pulse of
light. Accordingly, the features recited for the nerve stimulating device
300, such as its use for feedback involving FEV1 surrogates, control
of the heart rate and blood pressure, stimulation during selected phases
of the respiratory cycle, and preferred frequency of stimulation, apply
as well to the nerve stimulating device 800 and will not be repeated
here. The preferred parameters for each nerve stimulating device are
those that produce the effects described below in connection with the
detailed description our experiments.

[0141]In yet another embodiment of the invention, electrodes applied to
the surface of the neck, or to some other surface of the body, are used
to non-invasively deliver electrical energy to a nerve, instead of
delivering the energy to the nerve via a magnetic coil, mechanical
vibrations and/or pulses of light. In particular, the vagus nerve may be
been stimulated non-invasively using electrodes applied via leads to the
surface of the skin. For example, U.S. Pat. No. 7,340,299, entitled
Methods of indirectly stimulating the vagus nerve to achieve controlled
asystole, to John D. Puskas, discloses the stimulation of the vagus nerve
using electrodes placed on the neck of the patient, but that patent is
unrelated to the treatment of bronchoconstriction. Non-invasive
electrical stimulation of the vagus nerve has also been described in
Japanese patent application JP2009233024A with a filing date of Mar. 26,
2008, entitled Vagus Nerve Stimulation System, to Fukui Yoshihito, in
which a body surface electrode is applied to the neck to stimulate the
vagus nerve electrically. However, that application pertains to the
control of heart rate and is unrelated to the treatment of
bronchoconstriction.

[0142]Patent application US2010/0057154, entitled Device and Method for
the Transdermal Stimulation of a Nerve of the Human Body, to Dietrich et
al., discloses a non-invasive transcutaneous/transdermal method for
stimulating the vagus nerve, at an anatomical location where the vagus
nerve has paths in the skin of the external auditory canal. Their
non-invasive method involves performing electrical stimulation at that
location, using surface stimulators that are similar to those used for
peripheral nerve and muscle stimulation for treatment of pain
(transdermal electrical nerve stimulation), muscle training (electrical
muscle stimulation) and electroacupuncture of defined meridian points.
The method used in that application is similar to the ones used in U.S.
Pat. No. 4,319,584, entitled Electrical pulse acupressure system, to
McCall, for electroacupuncture; U.S. Pat. No. 5,514,175 entitled
Auricular electrical stimulator, to Kim et al., for the treatment of
pain; and U.S. Pat. No. 4,966,164, entitled Combined sound generating
device and electrical acupuncture device and method for using the same,
to Colsen et al., for combined sound/electroacupuncture. A related
application is US2006/0122675, entitled Stimulator for auricular branch
of vagus nerve, to Libbus et al. Similarly, U.S. Pat. No. 7,386,347,
entitled Electric stimulator for alpha-wave derivation, to Chung et al.,
described electrical stimulation of the vagus nerve at the ear. Patent
application US2008/0288016, entitled Systems and Methods for Stimulating
Neural Targets, to Amurthur et al., also discloses electrical stimulation
of the vagus nerve at the ear. However, none of the disclosures in these
patents or patent applications for electrical stimulation of the vagus
nerve at the ear are used to treat bronchoconstriction.

[0143]The present embodiment of the invention uses some of the methods and
devices for delivery of electrical energy to nerves via electrodes that
were previously disclosed in the commonly assigned co-pending U.S. patent
application Ser. No. 12/422,483, entitled Percutaneous Electrical
Treatment of Tissue, which is hereby incorporated by reference in its
entirety. FIG. 1 of that application illustrates a nerve stimulating
device that functions in a manner that is analogous to the nerve
stimulating device shown in FIG. 1 of the present invention, except that
electrical energy is applied to electrodes rather than to a coil.

[0144]In the present embodiment of the invention, a nerve stimulating
device delivers electrical impulses to nerves. The device may include an
electrical impulse generator; a power source coupled to the electrical
impulse generator; a control unit in communication with the electrical
impulse generator and coupled to the power source; and an electrode
assembly coupled to the electrical impulse generator for attachment via
lead to one or more selected regions of the patient's body. The control
unit may control the electrical impulse generator for generation of a
signal suitable for amelioration of a patient's condition when the signal
is applied via the electrode assembly to the nerve. It is noted that the
nerve modulating device may be referred to by its function as a pulse
generator. U.S. Patent Application Publications 2005/0075701 and
2005/0075702, both to Shafer, both of which are incorporated herein by
reference, relating to stimulation of neurons of the sympathetic nervous
system to attenuate an immune response, contain descriptions of pulse
generators that may be applicable to various embodiments of the present
invention.

[0145]The present invention differs from the one disclosed in the
above-mentioned commonly assigned co-pending U.S. patent application Ser.
No. 12/408,131 because in the present invention, the electrodes or their
corresponding leads are applied non-invasively to the surface of the neck
of the patient, or to some other surface of the body, thereby delivering
electrical energy to a nerve through the skin and through underlying
tissue that surrounds the nerve. Accordingly, what follows is a
disclosure of the configuration of the electrodes and their corresponding
leads when applied non-invasively to the surface of the skin. Preferred
embodiments of other aspects of the invention are as described below in
connection with the experiments that were conducted by the applicant and
that were disclosed in the co-pending U.S. patent application Ser. No.
12/408,131.

[0146]Proceeding from the skin of the neck above the sternocleidomastoid
muscle to the vagus nerve, a line would pass successively through the
sternocleidomastoid muscle, the carotid sheath and the internal jugular
vein, unless the position on the skin is immediately to either side of
the external jugular vein. In the latter case, the line may pass
successively through only the sternocleidomastoid muscle and the carotid
sheath before encountering the vagus nerve, missing the interior jugular
vein. Accordingly, a point on the neck adjacent to the external jugular
vein is the preferred location for non-invasive stimulation of the vagus
nerve. In the preferred embodiment, the electrode configuration would be
centered on such a point, at the level of about the fifth to sixth
cervical vertebra. Typically, the location of the carotid sheath or
jugular veins in a patient (and therefore the location of the vagus
nerve) will be ascertained in any manner known in the art, e.g., by feel
or ultrasound imaging.

[0147]Embodiments of the present invention differ with regard to the
number of electrodes that are used, the distance between electrodes, and
whether disk or ring electrodes are used. In the preferred embodiment of
the method, one selects the electrode configuration for individual
patients, in such a way as to optimally focus electric fields and
currents onto the selected nerve, without generating excessive currents
on the surface of the skin. The method describing this tradeoff between
focality and surface currents is as described by DATTA et al. [Abhishek
DATTA, Maged Elwassif, Fortunato Battaglia and Marom Bikson. Transcranial
current stimulation focality using disc and ring electrode
configurations: FEM analysis. J. Neural Eng. 5 (2008): 163-174]. The
present invention uses the electrode configurations that are listed in
that publication (bipolar, tripolar, concentric ring, and double
concentric ring, each having multiple separations and radii), except that
in our invention, elliptical ring electrodes are also used rather than
just circular ring electrodes, in which elliptical electrodes may have a
major axis that may be as large as ten times the length of the ellipse's
minor axis. When elliptical electrodes are used, the major axis of the
ellipse is aligned to be parallel with the axis of the nerve that is
selected for stimulation. Furthermore, the electrodes may fit the
curvature of patient's body surface, rather than be only planar. Although
DATTA et al. are addressing the selection of electrode configuration
specifically for transcranial current stimulation, the principles that
they describe are applicable to peripheral nerves as well [RATTAY F.
Analysis of models for extracellular fiber stimulation. IEEE Trans.
Biomed. Eng. 36 (1989): 676-682].

[0148]To implement the preferred embodiment, the user endeavors to
stimulate the selected nerve with a succession of electrode
configurations, beginning with the most focal configuration (e.g., the
one with the highest value of mDESCD/CSCD in Table 1 of the article by
DATTA et al.). For the initial configuration, the electrodes are centered
on the patient's neck at the above-mentioned preferred location, and the
maximum pulse current is slowly increased until the patient first feels
an uncomfortable sensation at the surface of the skin. The maximum pulse
current is then reduced by about 5 percent, and after about ten minutes
of stimulation, the effect of the stimulation is ascertained by measuring
the patient's FEV1 or any of its surrogate measurements that were
described above. If stimulation with that electrode configuration is not
successful in significantly increasing the patient's FEV1, the
electrode configuration is replaced with one that is less focal (e.g.,
the one with second to the highest value of mDESCD/CSCD in Table 1 of the
article by DATTA et al.). Again, the maximum pulse current is slowly
increased until the patient first feels an uncomfortable sensation at the
surface of the skin; the maximum pulse current is reduced by about 5
percent; and the effect of the stimulation is ascertained by measuring
the patient's FEV1 or any of the surrogate measurements described
above. If stimulation with that second electrode configuration is not
successful in significantly increasing the patient's FEV1, the
electrode configuration is again replaced with one that is less focal
(e.g., the one with third to the highest value of mDESCD/CSCD in Table 1
of the article by DATTA et al.). Proceeding in this manner, one may
eventually determine that there is an electrode configuration that
produces a significant increase in the patient's FEV1, without
generating excessive currents on the surface of the skin. In alternate
embodiments or the invention, the electrode configurations may be
successively more focal, or the electrode configurations may be
restricted to only one type (such as concentric ring), or distances and
diameters other than those listed by DATTA et al. may be used, or one may
select electrode configurations based on previous experience with a
patient.

[0149]Considering that the nerve stimulating device 300 in FIG. 1 and the
nerve stimulating device described above for use with electrodes both
control the shape of electrical impulses, their functions are analogous,
except that one stimulates nerves via a pulse of a magnetic field, and
the other stimulates nerves via an electrical pulse applied through
surface electrodes. Accordingly, the features recited for the nerve
stimulating device 300, such as its use for feedback involving FEV1
surrogates, control of the heart rate and blood pressure, stimulation
during selected phases of the respiratory cycle, and preferred frequency
of stimulation, apply as well to the latter stimulating device and will
not be repeated here. The preferred parameters for each nerve stimulating
device are those that produce the effects described below in connection
with the detailed description our experiments.

[0150]A general approach to treating bronchial constriction in accordance
with one or more embodiments of the invention is now described, before
discussing the details of applicant's experiments that were summarized
above. The general approach may include a method of (or apparatus for)
treating bronchial constriction associated with anaphylactic shock, COPD
or asthma, comprising applying at least one impulse of energy to one or
more selected nerve fibers of a mammal in need of relief of bronchial
constriction. The method may include applying one or more stimulation
signals to produce at least one impulse of energy, wherein the one or
more stimulation signals are of a frequency between about 15 Hz to 50 Hz.

[0151]The one or more stimulation signals may be of an amplitude
equivalent to between about 1-12 joules per coulomb of displaced charged
particles. The one or more stimulation signals may be one or more of a
full or partial sinusoid, square wave, rectangular wave, and/or triangle
wave. The one or more stimulation signals may have a pulsed on-time of
between about 50 to 500 microseconds, such as about 100, 200 or 400
microseconds. The polarity of the pulses may be maintained either
positive or negative. Alternatively, the polarity of the pulses may be
positive for some periods of the wave and negative for some other periods
of the wave. By way of example, the polarity of the pulses may be altered
about every second.

[0152]In one particular embodiment of the present invention, impulses of
energy are delivered to one or more portions of the vagus nerve. The
vagus nerve is composed of motor and sensory fibers. The vagus nerve
leaves the cranium and is contained in the same sheath of dura matter
with the accessory nerve. The vagus nerve passes down the neck within the
carotid sheath to the root of the neck. The branches of distribution of
the vagus nerve include, among others, the superior cardiac, the inferior
cardiac, the anterior bronchial and the posterior bronchial branches. On
the right side, the vagus nerve descends by the trachea to the back of
the root of the lung, where it spreads out in the posterior pulmonary
plexus. On the left side, the vagus nerve enters the thorax, crosses the
left side of the arch of the aorta, and descends behind the root of the
left lung, forming the posterior pulmonary plexus.

[0153]In mammals, two vagal components have evolved in the brainstem to
regulate peripheral parasympathetic functions. The dorsal vagal complex
(DVC), consisting of the dorsal motor nucleus (DMNX) and its connections,
controls parasympathetic function below the level of the diaphragm, while
the ventral vagal complex (VVC), comprised of nucleus ambiguus and
nucleus retrofacial, controls functions above the diaphragm in organs
such as the heart, thymus and lungs, as well as other glands and tissues
of the neck and upper chest, and specialized muscles such as those of the
esophageal complex.

[0154]The parasympathetic portion of the vagus innervates ganglionic
neurons which are located in or adjacent to each target organ. The VVC
appears only in mammals and is associated with positive as well as
negative regulation of heart rate, bronchial constriction,
bronchodilation, vocalization and contraction of the facial muscles in
relation to emotional states. Generally speaking, this portion of the
vagus nerve regulates parasympathetic tone. The VVC inhibition is
released (turned off) in states of alertness. This in turn causes cardiac
vagal tone to decrease and airways to open, to support responses to
environmental challenges.

[0155]The parasympathetic tone is balanced in part by sympathetic
innervations, which generally speaking supplies signals tending to relax
the bronchial muscles so overconstriction does not occur. Overall, airway
smooth muscle tone is dependent on several factors, including
parasympathetic input, inhibitory influence of circulating epinephrine,
iNANC nerves and sympathetic innervations of the parasympathetic ganglia.
Stimulation of certain nerve fibers of the vagus nerve (upregulation of
tone), such as occurs in asthma or COPD attacks or anaphylactic shock,
results in airway constriction and a decrease in heart rate. In general,
the pathology of severe asthma, COPD and anaphylaxis appear to be
mediated by inflammatory cytokines that overwhelm receptors on the nerve
cells and cause the cells to massively upregulate the parasympathetic
tone.

[0156]The methods described herein of applying an impulse of energy to a
selected region of the vagus nerve may further be refined such that the
at least one region may comprise at least one nerve fiber emanating from
the patient's tenth cranial nerve (the vagus nerve), and in particular,
at least one of the anterior bronchial branches thereof, or alternatively
at least one of the posterior bronchial branches thereof. Preferably the
impulse is provided to at least one of the anterior pulmonary or
posterior pulmonary plexuses aligned along the exterior of the lung. As
necessary, the impulse may be directed to nerves innervating only the
bronchial tree and lung tissue itself. In addition, the impulse may be
directed to a region of the vagus nerve to stimulate, block and/or
modulate both the cardiac and bronchial branches. As recognized by those
having skill in the art, this embodiment should be carefully evaluated
prior to use in patients known to have preexisting cardiac issues.

[0157]Experiments were performed to identify exemplary methods of how
signals, such as electrical signals, can be supplied to the peripheral
nerve fibers that innervate and/or control the bronchial smooth muscle to
(i) reduce the sensitivity of the muscle to the signals to constrict, and
(ii) to blunt the intensity of, or break the constriction once it has
been initiated. In particular, specific signals were applied to the
selected nerves in guinea pigs to produce selective stimulation,
interruption or reduction in the effects of nerve activity leading to
attenuation of histamine-induced bronchoconstriction.

[0158]Male guinea pigs (400 g) were transported to the lab and immediately
anesthetized with an i.p. injection of urethane 1.5 g/kg. Skin over the
anterior neck was opened and the carotid artery and both jugular veins
were cannulated with PE50 tubing to allow for blood pressure/heart rate
monitoring and drug administration, respectively. The trachea was
cannulated and the animal ventilated by positive pressure, constant
volume ventilation followed by paralysis with succinylcholine (10
ug/kg/min) to paralyze the chest wall musculature to remove the
contribution of chest wall rigidity from airway pressure measurements.

[0159]Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine
from nerve terminals that may interfere with the nerve stimulation. In
these experiments, vagus nerves were exposed and connected to electrodes
to allow selective stimuli of these nerves. Following 15 minutes of
stabilization, baseline hemodynamic and airway pressure measurements were
made before and after the administration of repetitive doses of i.v.
histamine.

[0160]Following the establishment of a consistent response to i.v.
histamine, nerve stimulation was attempted at variations of frequency,
voltage and pulse duration to identity parameters that attenuate
responses to i.v. histamine. Bronchoconstriction in response to i.v.
histamine is known to be due both to direct airway smooth muscle effects
and to stimulation of vagal nerves to release acetylcholine.

[0161]At the end of vagal nerve challenges, atropine was administered i.v.
before a subsequent dose of histamine to determine what percentage of the
histamine-induced bronchoconstriction was vagal nerve induced. This was
considered a 100% response. Success of electrical interruption in vagal
nerve activity in attenuating histamine-induced bronchoconstriction was
compared to this maximum effect. Euthanasia was accomplished with
intravenous potassium chloride.

[0162]In order to measure the bronchoconstriction, the airway pressure was
measured in two places. The blood pressure and heart rate were measured
to track the subjects' vital signs. In all the following graphs, the top
line BP shows blood pressure, second line AP1 shows airway pressure,
third line AP2 shows airway pressure on another sensor, the last line HR
is the heart rate derived from the pulses in the blood pressure.

[0163]In the first animals, the signal frequency applied was varied from
less than 1 Hz through 2,000 Hz, and the voltage was varied from 1V to
12V. Initial indications seemed to show that an appropriate signal was
1,000 Hz, 400 μs, and 6-10V.

[0164]FIG. 5 graphically illustrates exemplary experimental data on guinea
pig #2. More specifically, the graphs of FIG. 5 show the effect of a 1000
Hz, 400 μS, 6V square wave signal applied simultaneously to both left
and right branches of the vagus nerve in guinea pig #2 when injected with
12 μg/kg histamine to cause airway pressure to increase. The first
peak in airway pressure is histamine with the electric signal applied to
the vagus, the next peak is histamine alone (signal off), the third peak
is histamine and signal again, fourth peak is histamine alone again. It
is clearly shown that the increase in airway pressure due to histamine is
reduced in the presence of the 1000 Hz, 400 μS and 6V square wave on
the vagus nerve. The animal's condition remained stable, as seen by the
fact that the blood pressure and heart rate are not affected by this
electrical signal.

[0165]After several attempts on the same animal to continue to reproduce
this effect with the 1,000 Hz signal, however, we observed that the
ability to continuously stimulate and suppress airway constriction was
diminished, and then lost. It appeared that the nerve was no longer
conducting. This conclusion was drawn from the facts that (i) there was
some discoloration of the nerve where the electrode had been making
contact, and (ii) the effect could be resuscitated by moving the lead
distally to an undamaged area of the nerve, i.e. toward the organs, but
not proximally, i.e., toward the brain. The same thing occurred with
animal #3. It has been hypothesized that the effect seen was, therefore,
accompanied by a damaging of the nerve, which would not be clinically
desirable.

[0166]To resolve the issue, in the next animal (guinea pig #4), we
fabricated a new set of electrodes with much wider contact area to the
nerve. With this new electrode, we started investigating signals from 1
Hz to 3,000 Hz again. This time, the most robust effectiveness and
reproducibility was found at a frequency of 25 Hz, 400 μs, 1V.

[0167]FIG. 6 graphically illustrates exemplary experimental data on guinea
pig #5. The graphs of FIG. 6 show the effect of a 25 Hz, 400 μS, 1V
square wave signal applied to both left and right vagus nerve in guinea
pig #5 when injected with 8 μg/kg histamine to cause airway pressure
to increase. The first peak in airway pressure is from histamine alone,
the next peak is histamine and signal applied. It is clearly shown that
the increase in airway pressure due to histamine is reduced in the
presence of the 25 Hz, 400 μS, 1V square wave on the vagus nerve.

[0168]FIG. 7 graphically illustrates additional exemplary experimental
data on guinea pig #5. The graphs of FIG. 7 show the effect of a 25 Hz,
200 μS, 1V square wave signal applied to both of the left and right
vagus nerves in guinea pig #5 when injected with 8 μg/kg histamine to
cause airway pressure to increase. The second peak in airway pressure is
from histamine alone, the first peak is histamine and signal applied. It
is clearly shown that the increase in airway pressure due to histamine is
reduced in the presence of the 25 Hz, 200 μS, 1V square wave on the
vagus nerve. It is clear that the airway pressure reduction is even
better with the 200 μS pulse width than the 400 μS signal.

[0169]FIG. 8 graphically illustrates further exemplary experimental data
on guinea pig #5. The graphs of FIG. 8 show repeatability of the effect
seen in the previous graph. The animal, histamine and signal are the same
as the graphs in FIG. 7.

[0170]It is significant that the effects shown above were repeated several
times with this animal (guinea pig #5), without any loss of nerve
activity observed. We could move the electrodes proximally and distally
along the vagus nerve and achieve the same effect. It was, therefore,
concluded that the effect was being achieved without damaging the nerve.

[0172]This evidence strongly suggests that the increase in airway pressure
due to histamine can be significantly reduced by the application of a 25
Hz, 100 μS, 1V square wave with alternating polarity on the vagus
nerve.

[0173]FIG. 10 graphically illustrates exemplary experimental data on
guinea pig #6. The graphs in FIG. 10 show the effect of a 25 Hz, 200
μS, 1V square wave that switches polarity from + to - voltage every
second. This signal is applied to both left and right vagus nerve in
guinea pig #6 when injected with 16 μg/kg histamine to cause airway
pressure to increase. (Note that this animal demonstrated a very high
tolerance to the effects of histamine, and therefore was not an ideal
test subject for the airway constriction effects, however, the animal did
provide us with the opportunity to test modification of other signal
parameters.)

[0174]In this case, the first peak in airway pressure is from histamine
alone, the next peak is histamine with the signal applied. It is clearly
shown that the increase in airway pressure due to histamine is reduced
moderately in its peak, and most definitely in its duration, when in the
presence of the 25 Hz, 200 μS, 1V square wave with alternating
polarity on the vagus nerve.

[0175]FIG. 11 graphically illustrates additional exemplary experimental
data on guinea pig #6. As mentioned above, guinea pig #6 in the graphs of
FIG. 10 above needed more histamine than other guinea pigs (16-20
μg/kg vs 8 μg/kg) to achieve the desired increase in airway
pressure. Also, the beneficial effects of the 1V signal were less
pronounced in pig #6 than in #5. Consequently, we tried increasing the
voltage to 1.5V. The first airway peak is from histamine alone (followed
by a series of manual occlusions of the airway tube), and the second peak
is the result of histamine with the 1.5V, 25 Hz, 200 μS alternating
polarity signal. The beneficial effects are seen with slightly more
impact, but not substantially better than the 1V.

[0176]FIG. 12 graphically illustrates further exemplary experimental data
on guinea pig #6. Since guinea pig #6 was losing its airway reaction to
histamine, we tried to determine if the 25 Hz, 200 μS, 1V, alternating
polarity signal could mitigate the effects of a 20V, 20 Hz airway
pressure stimulating signal that has produced a simulated asthmatic
response. The first airway peak is the 20V, 20 Hz stimulator signal
applied to increase pressure, then switched over to the 25 Hz, 200 μS,
1V, alternating polarity signal. The second peak is the 20V, 20 Hz signal
alone. The first peak looks modestly lower and narrower than the second.
The 25 Hz, 200 μS, 1V signal may have some beneficial airway pressure
reduction after electrical stimulation of airway constriction.

[0177]FIG. 13 graphically illustrates subsequent exemplary experimental
data. On guinea pig #6 we also investigated the effect of the 1 V, 25 Hz,
and 200 μS alternating polarity signal. Even after application of the
signal for 10 minutes continuously, there was no loss of nerve conduction
or signs of damage.

[0178]FIG. 14 graphically illustrates exemplary experimental data on
guinea pig #8. The graph below shows the effect of a 25 Hz, 200 μS, 1V
square wave that switches polarity from + to - voltage every second. This
signal is applied to both left and right vagus nerve in guinea pig #8
when injected with 12 μg/kg histamine to cause airway pressure to
increase. The first peak in airway pressure is from histamine alone, the
next peak is histamine with the signal applied. It is clearly shown that
the increase in airway pressure due to histamine is reduced in the
presence of the 25 Hz, 200 μS, 1V square wave with alternating
polarity on the vagus nerve. We have reproduced this effect multiple
times, on 4 different guinea pigs, on 4 different days.

[0179]The airway constriction induced by histamine in guinea pigs can be
significantly reduced by applying appropriate electrical signals to the
vagus nerve. We found at least 2 separate frequency ranges that have this
effect. At 1000 Hz, 6V, 400 μS the constriction is reduced, but there
is evidence that this is too much power for the nerve to handle. This may
be mitigated by different electrode lead design in future tests.
Different types of animals also may tolerate differently differing power
levels.

[0180]With a 25 Hz, 1 V, 100-200 μS signal applied to the vagus nerve,
airway constriction due to histamine is significantly reduced. This has
been repeated on multiple animals many times. There is no evidence of
nerve damage, and the power requirement of the generator is reduced by a
factor of between 480 (40×6×2) and 960 (40×6×4)
versus the 1000 Hz, 6V, 400 μS signal.

[0181]In addition to the exemplary testing described above, further
testing on guinea pigs was made by applicant to determine the optimal
frequency range for reducing bronchoconstriction. These tests were all
completed similarly as above by first establishing a consistent response
to i.v. histamine, and then performing nerve stimulation at variations of
frequency, voltage and pulse duration to identity parameters that
attenuate responses to i.v. histamine. The tests were conducted on over
100 animals at the following frequency values: 1 Hz, 10 Hz, 15 Hz, 25 Hz,
50 Hz, 250 Hz, 500 Hz, 1000 Hz, 2000 Hz and 3000 Hz at pulse durations
from 0.16 ms to 0.4 ms with most of the testing done at 0.2 ms. In each
of the tests, applicant attempted to achieve a decrease in the histamine
transient. Any decrease was noted, while a 50% reduction in histamine
transient was considered a significant decrease.

[0182]The 25 Hz signal produced the best results by far with about 68% of
the animals tested (over 50 animals tested at this frequency) achieving a
reduction in histamine transient and about 17% of the animals achieving a
significant (i.e., greater than 50%) reduction. In fact, 25 Hz was the
only frequency in which any animal achieved a significant decrease in the
histamine transient. About 30% of the animals produced no effect and only
2% (one animal) resulted in an increase in the histamine transient.

[0183]The 15 Hz signal was tested on 18 animals and showed some positive
effects, although not as strong as the 25 Hz signal. Seven of the animals
(39%) demonstrated a small decrease in histamine transient and none of
the animals demonstrated an increase in histamine transient. Also, none
of the animals achieved a significant (greater than 50%) reduction as was
seen with the 25 Hz signal.

[0184]Frequency ranges below 15 Hz had little to no effect on the
histamine transient, except that a 1 Hz signal had the opposite effect on
one animal (histamine transient actually increased indicating a further
constriction of the bronchial passages). Frequency ranges at or above 50
Hz appeared to either have no effect or they increased the histamine
transient and thus increased the bronchoconstriction.

[0185]These tests demonstrate that applicant has made the surprising and
unexpected discovery that a signal within a small frequency band will
have a clinically significant impact on reducing the magnitude of
bronchial constriction on animals subject to histamine. In particular,
applicant has shown that a frequency range of about 15 Hz to about 50 Hz
will have some positive effect on counteracting the impact of histamine,
thereby producing bronchodilation. Frequencies outside of this range do
not appear to have any impact and, in some case, make the
bronchoconstriction worse. In particular, applicant has found that the
frequency signal of 25 Hz appears to be the optimal and thus preferred
frequency as this was the only frequency tested that resulted in a
significant decrease in histamine transient in at least some of the
animals and the only frequency tested that resulted in a positive
response (i.e., decrease in histamine transient) in at least 66% of the
treated animals.

[0186]FIGS. 15-18 graphically illustrate exemplary experimental data
obtained on five human patients in accordance with multiple embodiments
of the present invention. In the first patient (see FIGS. 15 and 16), a
34 year-old, Hispanic male patient with a four year history of severe
asthma was admitted to the emergency department with an acute asthma
attack. He reported self treatment with albuterol without success. Upon
admission, the patient was alert and calm but demonstrated bilateral
wheezing, elevated blood pressure (BP) (163/92 mmHg) related to chronic
hypertension, acute bronchitis, and mild throat hyperemia. All other
vital signs were normal. The patient was administered albuterol (2.5 mg),
prednisone (60 mg PO), and zithromax (500 mg PO) without improvement. The
spirometry assessment of the lung function revealed a Forced Expiratory
Volume in 1 second (FEV1) of 2.68 l/min or 69% of predicted.
Additional albuterol was administered without benefit and the patient was
placed on supplemental oxygen (2 l/min).

[0187]A study entailing a new investigational medical device for
stimulating the selected nerves near the carotid sheath was discussed
with the patient and, after review, the patient completed the Informed
Consent. Following a 90 minute observational period without notable
improvement in symptoms, the patient underwent placement of a
percutaneous, bipolar electrode to stimulate the selected nerves (see
FIG. 16). Using anatomical landmarks and ultrasound guidance, the
electrode was inserted to a position near the carotid sheath, and
parallel to the vagus nerve.

[0188]The electrode insertion was uneventful and a subthreshold test
confirmed the device was functioning. Spirometry was repeated and
FEV1 remained unchanged at 2.68 l/min. Stimulation (25 Hz, 300
microsecond pulse width signal) strength was gradually increased until
the patient felt a mild muscle twitch at 7.5 volts then reduced to 7
volts. This setting achieved therapeutic levels without discomfort and
the patient was able to repeat the FEV1 test without difficulty.
During stimulation, the FEV1 improved immediately to 3.18 l/min and
stabilized at 3.29 l/min (85% predicted) during 180 minutes of testing.
The benefit remained during the first thirty minutes after terminating
treatment, then decreased. By 60 minutes post stimulation, dyspnea
returned and FEV1 decreased to near prestimulation levels (73%
predicted) (FIG. 2). The patient remained under observation overnight to
monitor his hypertension and then discharged. At the 1-week follow-up
visit, the exam showed complete healing of the insertion site, and the
patient reported no after effects from the treatment.

[0189]This was, to the inventor's knowledge, the first use of nerve
stimulation in a human asthma patient to treat bronchoconstriction. In
the treatment report here, invasive surgery was not required. Instead a
minimally invasive, percutaneous approach was used to position an
electrode in close proximity to the selected nerves. This was a
relatively simple and rapid procedure that was performed in the emergency
department and completed in approximately 10 minutes without evidence of
bleeding or scarring.

[0190]FIG. 17 graphically illustrates another patient treated according to
the present invention. Increasing doses of methacholine were given until
a drop of 24% in FEV1 was observed at 1 mg/ml. A second FEV1
was taken prior to insertion of the electrode. The electrode was then
inserted and another FEV1 taken after electrode insertion and before
stimulation. The stimulator was then turned on to 10 V for 4 minutes, the
electrode removed and a post-stimulation FEV1 taken showing a 16%
increase. A final rescue albuterol treatment restored normal FEV1

[0191]FIG. 18 is a table summarizing the results of all five human
patients. In all cases, FEV1 values were measured prior to
administration of the electrical impulse delivery to the patient
according to the present invention. In addition, FEV1 values were
measures at every 15 minutes after the start of treatment. A 12% increase
in FEV1 is considered clinically significant. All five patients
achieved a clinically significant increase in FEV1 of 12% or greater
in 90 minutes or less, which represents a clinically significant increase
in an acute period of time. In addition, all five patients achieved at
least a 19% increase in FEV1 in 150 minutes or less.

[0192]As shown, the first patient initially presented with an FEV1 of
61% of predicted. Upon application of the electrical impulse described
above, the first patient achieved at least a 12% increase in FEV1 in
15 minutes or less and achieved a peak increase in FEV1 of 43.9%
after 75 minutes. The second patient presented with an FEV1 of 51%
of predicted, achieved at least a 12% increase in FEV1 in 30 minutes
or less and achieved a peak increase in FEV1 of 41.2% after 150
minutes. The third patient presented with an FEV1 of 16% of
predicted, achieved at least a 12% increase in FEV1 in 15 minutes or
less and achieved a peak increase in FEV1 of about 131.3% in about
150 minutes. However, it should be noted that this patient's values were
abnormal throughout the testing period. The patient was not under extreme
duress as a value of 16% of predicted would indicate. Therefore, the
exact numbers for this patient are suspect, although the patient's
symptoms clearly improved and the FEV1 increased in any event. The
fourth patient presented with an FEV1 of predicted of 66%, achieved
at least a 12% increase in FEV1 in 90 minutes or less and achieved a
peak increase in FEV1 of about 19.7% in 90 minutes or less.
Similarly, the fifth patient presented with an FEV1 of predicted of
52% and achieved a 19.2% peak increase in FEV1 in 15 minutes or
less. The electrode in the fifth patient was unintentionally removed
around 30 minutes after treatment and, therefore, a true peak increase in
FEV1 was not determined.

[0193]In U.S. patent application Ser. No. 10/990,938 filed Nov. 17, 2004
(Publication Number US2005/0125044A1), Kevin J. Tracey proposes a method
of treating many diseases including, among others, asthma, anaphylactic
shock, sepsis and septic shock by electrical stimulation of the vagus
nerve. However, the examples in the Tracey application use an electrical
signal that is 1 to 5V, 1 Hz and 2 mS to treat endotoxic shock, and no
examples are shown that test the proposed method on an asthma model, an
anaphylactic shock model, or a sepsis model. The applicants of the
present application performed additional testing to determine if Tracey's
proposed method has any beneficial effect on asthma or blood pressure in
the model that shows efficacy with the method used in the present
application. The applicants of the present application sought to
determine whether Tracey's signals can be applied to the vagus nerve to
attenuate histamine-induced bronchoconstriction and increase in blood
pressure in guinea pigs.

[0194]Male guinea pigs (400 g) were transported to the lab and immediately
anesthetized with an i.p. injection of urethane 1.5 g/kg. Skin over the
anterior neck was opened and the carotid artery and both jugular veins
are cannulated with PE50 tubing to allow for blood pressure/heart rate
monitoring and drug administration, respectively. The trachea was
cannulated and the animal ventilated by positive pressure, constant
volume ventilation followed by paralysis with succinylcholine (10
ug/kg/min) to paralyze the chest wall musculature to remove the
contribution of chest wall rigidity from airway pressure measurements.

[0195]Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine
from nerve terminals that may interfere with vagal nerve stimulation.
Both vagus nerves were exposed and connected to electrodes to allow
selective stimuli of these nerves. Following 15 minutes of stabilization,
baseline hemodynamic and airway pressure measurements were made before
and after the administration of repetitive doses of i.v. histamine.

[0196]Following the establishment of a consistent response to i.v.
histamine, vagal nerve stimulation was attempted at variations of 1 to 5
volts, 1 Hz, 2 mS to identity parameters that attenuate responses to i.v.
histamine. Bronchoconstriction in response to i.v. histamine is known to
be due to both direct airway smooth muscle effects and due to stimulation
of vagal nerves to release acetylcholine.

[0197]At the end of vagal nerve challenges atropine was administered i.v.
before a subsequent dose of histamine to determine what percentage of the
histamine-induced bronchoconstriction was vagal nerve induced. This was
considered a 100% response. Success of electrical interruption in vagal
nerve activity in attenuating histamine-induced bronchoconstriction was
compared to this maximum effect. Euthanasia was accomplished with
intravenous potassium chloride.

[0198]In order to measure the bronchoconstriction, the airway pressure was
measured in two places. The blood pressure and heart rate were measured
to track the subjects' vital signs.

[0199]In all the following graphs, the top line BP (red) shows blood
pressure, second line AP1 shows airway pressure, third line AP2 shows
airway pressure on another sensor, the last line HR is the heart rate
derived from the pulses in the blood pressure.

[0200]FIG. 19 graphically illustrates exemplary experimental data from a
first experiment on another guinea pig. The graph shows the effects of
Tracey's 1V, 1 Hz, 2 mS waveform applied to both vagus nerves on the
guinea pig. The first peak in airway pressure is from histamine alone,
after which Tracey's signal was applied for 10 minutes as proposed in
Tracey's patent application. As seen from the second airway peak, the
signal has no noticeable effect on airway pressure. The animal's vital
signs actually stabilized, seen in the rise in blood pressure, after the
signal was turned off.

[0201]FIG. 20 graphically illustrates exemplary experimental data from a
second experiment on the guinea pig in FIG. 19. The graph shows the
effects of Tracey's 1V, 1 Hz, 2 mS waveform with the polarity reversed
(Tracey did not specify polarity in the patent application) applied to
both vagus nerves on the guinea pig. Again, the signal has no beneficial
effect on airway pressure. In fact, the second airway peak from the
signal and histamine combination is actually higher than the first peak
of histamine alone.

[0202]FIG. 21 graphically illustrates exemplary experimental data from a
third experiment on the guinea pig in FIG. 19. The graph shows the
effects of Tracey's 1V, 1 Hz, 2 mS waveform applied to both vagus nerves
on the guinea pig. Again, the signal has no beneficial effect on airway
pressure. Instead, it increases airway pressure slightly throughout the
duration of the signal application.

[0203]FIG. 22 graphically illustrates additional exemplary experimental
data from an experiment on a subsequent guinea pig. The graph shows, from
left to right, application of the 1.2V, 25 Hz, 0.2 mS signal disclosed in
the present application, resulting in a slight decrease in airway
pressure in the absence of additional histamine. The subsequent three
electrical stimulation treatments are 1 V, 5V, and 2.5V variations of
Tracey's proposed signal, applied after the effects of a histamine
application largely had subsided. It is clear that the Tracey signals do
not cause a decrease in airway pressure, but rather a slight increase,
which remained and progressed over time.

[0204]FIG. 23 graphically illustrates further exemplary experimental data
from additional experiments using signals within the range of Tracey's
proposed examples. None of the signals proposed by Tracey had any
beneficial effect on airway pressure. Factoring in a potential range of
signals, one experiment used 0.75V, which is below Tracey's proposed
range, but there was still no beneficial effect on airway pressure.

[0205]FIG. 24 graphically illustrates exemplary experimental data from
subsequent experiments showing the effect of Tracey's 5V, 1 Hz, 2 mS
signal, first without and then with additional histamine. It is clear
that the airway pressure increase is even greater with the signal, as the
airway pressure progressively increased during the course of signal
application. Adding the histamine after prolonged application of the
Tracey signal resulted in an even greater increase in airway pressure.

[0206]The full range of the signal proposed by Tracey in his patent
application was tested in the animal model of the present application. No
reduction in airway pressure was seen. Most of the voltages resulted in
detrimental increases in airway pressure and detrimental effects to vital
signs, such as decreases in blood pressure.

[0207]In International Patent Application Publication Number WO 93/01862,
filed Jul. 22, 1992, Joachim Wernicke and Reese Terry (hereinafter
referred to as "Wernicke") propose a method of treating respiratory
disorders such as asthma, cystic fibrosis and apnea by applying electric
signals to the patient's vagus nerve. However, Wernicke specifically
teaches to apply a signal that blocks efferent activity in the vagus
nerve to decrease the activity of the vagus nerve to treat asthma.
Moreover, the example disclosed in Wernicke for the treatment of asthma
is an electrical impulse having a frequency of 100 Hz, a pulse width of
0.5 ms, an output current of 1.5 mA and an OFF time of 10 seconds for
every 500 seconds of ON time (see Table 1 on page 17 of Wernicke). The
applicants of the present application performed additional testing to
determine if Wernicke's proposed method has any beneficial effect on
bronchodilation or blood pressure in the model that shows efficacy with
the method used in the present application. The applicants of the present
application sought to determine whether Wernicke's signal can be applied
to the vagus nerve to attenuate histamine-induced bronchoconstriction and
increase in blood pressure in guinea pigs.

[0208]Similar to the Tracey testing, male guinea pigs (400 g) were
transported to the lab and immediately anesthetized with an i.p.
injection of urethane 1.5 g/kg. Skin over the anterior neck was opened
and the carotid artery and both jugular veins are cannulated with PE50
tubing to allow for blood pressure/heart rate monitoring and drug
administration, respectively. The trachea was cannulated and the animal
ventilated by positive pressure, constant volume ventilation followed by
paralysis with succinylcholine (10 ug/kg/min) to paralyze the chest wall
musculature to remove the contribution of chest wall rigidity from airway
pressure measurements.

[0209]Guanethidine (10 mg/kg i.v.) was given to deplete norepinephrine
from nerve terminals that may interfere with vagal nerve stimulation.
Both vagus nerves were exposed and connected to electrodes to allow
selective stimuli of these nerves. Following 15 minutes of stabilization,
baseline hemodynamic and airway pressure measurements were made before
and after the administration of repetitive doses of i.v. histamine.

[0210]Following the establishment of a consistent response to i.v.
histamine, vagal nerve stimulation was attempted at variations of 100 Hz,
0.5 ms and 1.5 mA output current to identity parameters that attenuate
responses to i.v. histamine. Bronchoconstriction in response to i.v.
histamine is known to be due to both direct airway smooth muscle effects
and due to stimulation of vagal nerves to release acetylcholine.

[0211]At the end of vagal nerve challenges atropine was administered i.v.
before a subsequent dose of histamine to determine what percentage of the
histamine-induced bronchoconstriction was vagal nerve induced. This was
considered a 100% response. Success of electrical interruption in vagal
nerve activity in attenuating histamine-induced bronchoconstriction was
compared to this maximum effect. Euthanasia was accomplished with
intravenous potassium chloride.

[0212]In order to measure the bronchoconstriction, the airway pressure was
measured in two places. The blood pressure and heart rate were measured
to track the subjects' vital signs. In all the following graphs, the top
line BP (red) shows blood pressure, second line AP1 shows airway
pressure, third line AP2 shows airway pressure on another sensor, the
last line HR is the heart rate derived from the pulses in the blood
pressure.

[0213]FIGS. 25 and 26 graphically illustrate exemplary experimental data
from the experiment on another guinea pig. The graph shows the effects of
Wernicke's 100 Hz, 1.5 mA, 0.5 mS waveform applied to both vagus nerves
on the guinea pig. FIG. 25 illustrates two peaks in airway pressure (AP)
from histamine alone with no treatment (the first two peaks) and a third
peak at the right of the graph after which Wernicke's signal was applied
at 1.2 mA. As shown, the results show no beneficial result on the
histamine-induced airway pressure increase or the blood pressure at 1.2
mA. In FIG. 26, the first and third peaks in airway pressure (AP) are
from histamine along with no treatment and the second peak illustrates
airway pressure after Wernicke's signal was applied at 1.8 mA. As shown,
the signal actually increased the histamine-induced airway pressure at
2.8 mA, making it clinically worse. Thus, it is clear the Wernicke
signals do not cause a decrease in airway pressure.

[0214]Although the invention herein has been described with reference to
particular embodiments, it is to be understood that these embodiments are
merely illustrative of the principles and applications of the present
invention. It is therefore to be understood that numerous modifications
may be made to the illustrative embodiments and that other arrangements
may be devised without departing from the spirit and scope of the present
invention as defined by the appended claims.